Showing papers in "The Journal of Clinical Pharmacology in 2021"
TL;DR: In this article, the authors presented 6 cases of acute hypersensitivity to polyethylene glycol (PEG) and demonstrated that PEG was the common culprit in these cases.
Abstract: Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods It acts as an inert bulking, or stabilizing, agent Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low We present 6 cases of acute hypersensitivity to PEG Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit All cases were female, with a mean age of 364 years Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema Biphasic allergic reactions featured prominently in this case series Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy
37 citations
TL;DR: Baricitinib is a JAK1/2 inhibitor that was first approved for treating moderate to severe rheumatoid arthritis (RA) but later showed considerable efficacy in the control of exaggerated inflammatory responses that occur in a wide range of diseases as discussed by the authors.
Abstract: Baricitinib is a JAK1/2 inhibitor that was first approved for treating moderate to severe rheumatoid arthritis (RA) but that later showed considerable efficacy in the control of exaggerated inflammatory responses that occur in a wide range of diseases. There is a growing body of evidence, obtained from clinical trials and case reports, demonstrating clinical and paraclinical improvement in patients following administration of baricitinib including RA, systemic lupus erythematosus, psoriasis, atopic dermatitis, alopecia areata, interferon-mediated autoinflammatory diseases, graft-versus-host disease, diabetic kidney disease, and, recently, coronavirus disease-19. However, despite overall encouraging results, many adverse effects have been observed in baricitinib-treated patients, ranging from simple infections to increased risk of malignancies, particularly in long-term use. The significant efficacy of baricitinib, versus the probable adverse effects, urge further investigation before establishing it as a part of standard therapeutic protocols. Here, we have provided a review of the studies that have used baricitinib for treating various inflammatory disorders and summarized the advantages and disadvantages of its administration.
24 citations
TL;DR: Considering both postnatal age and gestational age at birth in GFR ontogeny models is important because postmenstrual age alone ignores the impact of birth, and most GFR models use covariates of body size in addition to age.
Abstract: Glomerular filtration rate (GFR) is an important measure of renal function. Various models for its maturation have recently been compared; however, these have used markers, which are subject to different renal elimination processes. Inulin clearance data (a purer probe of GFR) collected from the literature were used to determine age-related changes in GFR aspects of renal drug excretion in pediatrics. An ontogeny model was derived using a best-fit model with various combinations of covariates such as postnatal age, gestational age at birth, and body weight. The model was applied to the prediction of systemic clearance of amikacin, gentamicin, vancomycin, and gadobutrol. During neonatal life, GFR increased as a function of both gestational age at birth and postnatal age, hence implying an impact of birth and a discrepancy in GFR for neonates with the same postmenstrual age depending on gestational age at birth (ie, neonates who were outside the womb longer had higher GFR, on average). The difference in GFR between pre-term and full-term neonates with the same postmenstrual age was negligible from beyond 1.25 years. Considering both postnatal age and gestational age at birth in GFR ontogeny models is important because postmenstrual age alone ignores the impact of birth. Most GFR models use covariates of body size in addition to age. Therefore, prediction from these models will also depend on the change in anthropometric characteristics with age. The latter may not be similar in various ethnic groups, and this makes the head-to-head comparison of models very challenging.
23 citations
TL;DR: Higher RO was associated with greater CRP reduction and 28‐joint Disease Activity Score based onCRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses.
Abstract: We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy (RO) and C-reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL-6Rα binding and signaling inhibition with sarilumab and tocilizumab in vitro, simulated soluble IL-6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28-joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL-6Rα in vitro with 15- to 22-fold higher affinity than tocilizumab, and inhibits IL-6-mediated classical and trans signaling via membrane-bound and soluble IL-6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady-state trough, RO was greater with sarilumab 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28-joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements.
23 citations
TL;DR: The effects of stimulants such as amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), or mephedrone can act on the neuronal membrane monoamine transporters NET, DAT, and SERT and/or the vesicular monoamine transporter 2 as discussed by the authors.
Abstract: Psychostimulant, cardiovascular, and temperature actions of stimulants involve adrenergic (norepinephrine), dopaminergic (dopamine), and serotonergic (serotonin) pathways. Stimulants such as amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), or mephedrone can act on the neuronal membrane monoamine transporters NET, DAT, and SERT and/or the vesicular monoamine transporter 2 to inhibit reuptake of neurotransmitter or cause release by reverse transport. Stimulants may have additional effects involving pre- and postsynaptic/junctional receptors for norepinephrine, dopamine, and serotonin and other receptors. As a result, stimulants may have a wide range of possible actions. Agents with cocaine or MDMA-like actions can induce serious and potentially fatal adverse events via thermodysregulatory, cardiovascular, or other mechanisms. MDMA-like stimulants may cause hyperthermia that can be life threathening. Recreational users of stimulants should be aware of the dangers of hyperthermia in a rave/club environment.
19 citations
TL;DR: This review performed this review to categorize the coronavirus disease 2019 potential therapeutics and vaccines to guide the clinicians to select the proper medications according to each patient's condition.
Abstract: Since the early days of 2020, the severe acute respiratory syndrome coronavirus 2 pandemic has become a global health concern. Currently, some therapies and vaccines have received US Food and Drug Administration approval or emergency use authorization for the management of coronavirus disease 2019. According to the pathophysiology of the disease, several medications have been evaluated in different clinical conditions of the disease. Evidence-based reviewing and categorizing these medications can guide the clinicians to select the proper medications according to each patient's condition. Therefore, we performed this review to categorize the coronavirus disease 2019 potential therapeutics and vaccines.
18 citations
TL;DR: In this article, the effect of renal impairment on the pharmacokinetics, safety, and tolerability of abrocitinib and its metabolites following a 200mg oral dose was investigated.
Abstract: Abrocitinib, an oral once-daily Janus kinase 1 selective inhibitor, is under development for the treatment of atopic dermatitis. This phase 1, nonrandomized, open-label, single-dose study (NCT03660241) investigated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of abrocitinib and its metabolites following a 200-mg oral dose. Twenty-three subjects with varying degrees of renal function (normal, moderate, and severe impairment) were enrolled. Active moiety exposures were calculated as the sum of unbound exposures for abrocitinib and its active metabolites. For abrocitinib, the adjusted geometric mean ratios (GMRs; %) for area under the concentration-time curve from time 0 extrapolated to infinite time (AUCinf ) and maximum plasma concentration (Cmax ) were 182.91 (90% CI, 117.09-285.71) and 138.49 (93.74-204.61), respectively, for subjects with moderate renal impairment versus normal renal function; corresponding GMRs were 121.32 (68.32-215.41) and 99.11 (57.30-171.43) for subjects with severe impairment versus normal renal function. Metabolite exposures generally increased in subjects with renal impairment. The GMRs of unbound AUCinf and Cmax of active moiety were 210.20 (154.60-285.80) and 133.87 (102.45-174.92), respectively, for subjects with moderate renal impairment versus normal renal function. Corresponding values were 290.68 (217.39-388.69) and 129.49 (92.86-180.57) for subjects with severe renal impairment versus normal renal function. Abrocitinib was generally safe and well tolerated. Both moderate and severe renal impairment led to higher exposure to abrocitinib active moiety, suggesting that abrocitinib dose should be reduced by half for patients with moderate or severe renal impairment. ClinicalTrials.gov identifier: NCT03660241 This article is protected by copyright. All rights reserved.
18 citations
TL;DR: The authors in this paper reviewed the epidemiology of addiction in the United States, including changes in use patterns over time, highlighting rates in adolescents and young adults, as well as adults.
Abstract: Many Americans use alcohol and recreational drugs. Some will develop substance use disorders that affect a person's brain and behavior, leading to continued use despite problems caused. We review the epidemiology of addiction in the United States, including changes in use patterns over time, highlighting rates in adolescents and young adults, as well as adults. An overview of the health and societal impacts of substance use is provided alongside the importance of multimodal, evidence-based treatment comprising psychosocial interventions and medication management. The article concludes by exploring the impact of the coronavirus disease 2019 pandemic on people who use drugs and their access to treatment.
17 citations
TL;DR: There is no evidence to justify the use of ARVs for prophylaxis against COVID‐19, despite the promising results of molecular studies and limited clinical evidence for ritonavir‐boosted lopinavir, darunavir, and nelfinavir when used early in the course of the disease.
Abstract: Although people living with human immunodeficiency virus and other comorbidities are expected to experience more grievous consequences with corona virus disease 2019 (COVID-19), recent cohort studies did not indicate this. Antiretrovirals (ARVs) might have a prophylactic role in these patients. The purpose of this study was to review the most recently published articles on the possible role of ARVs for pre- or postexposure prophylaxis against COVID-19. From June to October 2020, we searched scientific databases using specific key words to identify ongoing trials or articles published before October 2020 investigating any subgroups of ARVs for prophylaxis against COVID-19. Apart from molecular docking studies, in vitro, animal, and human studies are very limited for evaluating the prophylactic role of ARVs against severe acute respiratory syndrome-corona virus 2 (SARS-CoV-2) infection. According to our findings, there is no definite evidence to support use of protease inhibitors for this purpose, despite the promising results of molecular studies and limited clinical evidence for ritonavir-boosted lopinavir, darunavir, and nelfinavir when used early in the course of the disease. Nucleotide/nucleoside reverse-transcriptase inhibitors (NRTI) also have shown binding affinity to main enzymes of SARS-CoV-2 in molecular, in vitro, and animal studies. NRTIs like tenofovir and emtricitabine might exhibit a prophylactic role against SARS-CoV-2 infection. In conclusion, currently there is no evidence to justify the use of ARVs for prophylaxis against COVID-19.
17 citations
TL;DR: In this article, the use of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in the treatment of posttraumatic stress disorder (PTSD) was discussed.
Abstract: This article discusses current literature on the use of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in the treatment of posttraumatic stress disorder (PTSD). MDMA, the intended active ingredient in illicit Ecstasy or Molly products, is a psychedelic that causes an elevated mood, feeling of bonding, and increased energy. In MDMA-assisted psychotherapy, patients are subjected to 2 or 3 multihour sessions of therapy with a team of psychiatrists. The dosing of MDMA is used to allow the therapist to probe the underlying trauma without causing emotional distress. The use of MDMA-assisted psychotherapy treatment reduced patient's Clinician-Administered PTSD Scale (CAPS) scores from baseline more than control psychotherapy (-22.03; 95%CI, -38.53 to -5.52) but with high statistical heterogeneity. MDMA-assisted psychotherapy enhanced the achievement of clinically significant reductions in CAPS scores (relative risk, 3.65; 95%CI, 2.39-5.57) and CAPS score reductions sufficient to no longer meet the definition of PTSD (relative risk, 2.10; 95%CI, 1.37-3.21) with no detected statistical heterogeneity. While therapy was generally safe and well tolerated, bruxism, anxiety, jitteriness, headache, and nausea are commonly reported. While MDMA-assisted psychotherapy has been shown to be an effective therapy for patients with PTSD with a reasonable safety profile, use of unregulated MDMA or use in the absence of a strongly controlled psychotherapeutic environment has considerable risks.
16 citations
TL;DR: This study found a disproportionately high number of cases of bladder cancer among users of SGLT2is, however, observational analytical studies will be needed to confirm these results.
Abstract: The association between sodium-glucose cotransporter 2 inhibitors (SGLT2is) and cancer risk is unclear. The objective of this study was to analyze whether a disproportionate number of cases of bladder cancer are reported for SGLT2is in EudraVigilance. A case/noncase study was conducted to assess the association between bladder cancer and SGLT2is, calculating reporting odds ratios (RORs) from November 11, 2012 (approval date for the first SGLT2i, dapagliflozin) to May 19, 2020. First, cases involving SGLT2is were compared with those involving all other drugs; and similar analysis was performed for each SGLT2i. Second, to reduce the risk of confounding by indication, the RORs for SGLT2is compared with other antidiabetics were obtained. Besides, 2 measures were taken to evaluate a possible notoriety bias: a sensitivity analysis excluding pioglitazone was performed and the evolution of the ROR over time for SGLT2is was measured. There were 6602 cases of bladder cancer in the 4,213,637 reports during the study period. SGLT2is were involved in 155 cases. The ROR for pooled SGLT2is was 3.97 (95% confidence interval [CI], 3.39-4.66), disproportionality also being observed for each SGLT2i separately. The association was strongest for dapagliflozin (ROR, 7.02; 95%CI, 5.69-8.66). Nonetheless, this association disappeared when comparing SGLT2is with other antidiabetic drugs (ROR, 0.20; 95%CI, 0.17-0.24). But when excluding pioglitazone from the analysis, a safety signal for SGLT2is compared with other antidiabetics emerged (ROR, 6.84; 95%CI 5.41-8.65). Our study found a disproportionately high number of cases of bladder cancer among users of SGLT2is. However, observational analytical studies will be needed to confirm these results.
TL;DR: CD33 is a transmembrane protein that is found on cells of myeloid lineage that internalizes on binding and dimerization, making it a specific and ideal target for AML therapeutics and drug delivery.
Abstract: CD33 is a transmembrane protein that is found on cells of myeloid lineage. It is also intensely expressed on acute myeloid leukemia (AML) progenitor cells but not on normal stem cells. It internalizes on binding and dimerization, making it a specific and ideal target for AML therapeutics and drug delivery. Several targeted therapies have been tested and many are still currently in development. Gemtuzumab ozogamicin was the first and only CD33-directed antibody-drug conjugate to be US Food and Drug Administration approved for AML. Other targeted agents have not achieved such success. Promising new strategies include cellular therapy mechanisms and linker molecules. This is an exciting target that requires a considerable amount of precision to yield clinical benefit.
TL;DR: In this article, the authors discuss the potential role of e-cigarettes as smoking cessation aids, although many continue to use E-cigarettes long after quitting smoking, and discuss the implications of clinical pharmacology data on ENDS for the cigarette endgame and regulation by the U.S. Food and Drug administration.
Abstract: Electronic nicotine delivery systems (ENDS) such as e-cigarettes and heated tobacco products are novel battery-operated devices that deliver nicotine without combustion of tobacco. Because cigarette smoking is sustained by nicotine addiction and the toxic combustion products are mainly responsible for the harmful effects of smoking, ENDS could be used to promote smoking cessation while exposing users to lower levels of toxicants compared with conventional cigarettes. The currently available evidence from clinical and observational studies indicates a potential role of e-cigarettes as smoking cessation aids, although many continue to use e-cigarettes long after quitting smoking. Nicotine and toxicant delivery vary considerably by device and depend on the characteristics of the e-liquid formulation. Because smokers tend to titrate their nicotine intake to maintain their desired pharmacologic effects, device and liquid characteristics need to be considered when using ENDS as an aid to quit smoking. Factors potentially limiting their use are the currently still unknown long-term safety of these products and concerns regarding widespread use among youth. Implications of clinical pharmacology data on ENDS for the cigarette endgame and regulation by the U.S. Food and Drug administration are discussed.
TL;DR: In this paper, the authors investigated the health-related quality of life outcomes of patients with chronic pain who were prescribed CBMP oil preparations (Adven®, Curaleaf International) at 1, 3, and 6 months.
Abstract: Cannabis-based medicinal products (CBMPs) are an emerging therapeutic option in the management of primary chronic pain, utilizing the role of the endocannabinoid system in modulating central and peripheral pain processes. Despite promising pre-clinical data there is a paucity of high-quality evidence to support the use of CBMPs for chronic pain. This study aimed to investigate the health-related quality of life outcomes of patients with chronic pain who were prescribed CBMP oil preparations (Adven®, Curaleaf International) This study is a case-series of patients from the UK Medical Cannabis Registry, who were treated with CBMP oils for an indication of chronic pain. The primary outcomes were the changes in Brief Pain Inventory short-form (BPI), Short-form McGill Pain Questionnaire-2 (SF-MPQ-2), Visual Analogue Scale (VAS) Pain, General Anxiety Disorder-7 (GAD-7), Sleep Quality Scale (SQS), and EQ-5D-5L, at 1, 3, and 6 months. 110 patients were included. Significant improvements in SQS, EQ-5D-5L pain and discomfort subscale, and Brief Pain Inventory Interference Subscale (p<0.05) at 1, 3, and 6 months were demonstrated. There were no notable differences between cannabis naive and previous cannabis users in quality-of-life outcomes. The adverse event incidence was 30.0%, with most (n = 58, 92.1%) adverse events being mild or moderate in intensity. Treatment of chronic pain with Adven® CBMP oils was associated with an improvement in pain-specific outcomes, HRQoL and self-reported sleep quality. Relative safety was demonstrated over medium-term prescribed use. Whilst these findings must be treated with caution considering the limitations of study design, they can inform future clinical trials. This article is protected by copyright. All rights reserved.
TL;DR: Prescribers should attempt to use the same classification system in the product label for dosing decisions when Child‐Pugh is used for HI study enrollment and exploratory PK analyses based on NCIc are conducted.
Abstract: Guidance from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency recommends using Child-Pugh classification for pharmacokinetic evaluation in noncancer subjects with hepatic impairment (HI). Therefore, dosing recommendations for oncology compounds for patients with HI are commonly based on Child-Pugh classification. In oncology clinical practice, National Cancer Institute classification (NCIc), is commonly used for evaluating hepatic function and dosing decisions for oncology patients. This work evaluated the discordance between the 2 systems and the impact on dosing recommendations. The classification system in HI studies was reviewed for FDA-approved oncology compounds. Discordance between Child-Pugh and NCIc was evaluated for sunitinib, dacomitinib, palbociclib, bosutinib, and axitinib. Pharmacokinetic (PK) analyses were conducted based on Child-Pugh classification and NCIc. Review of 117 approved oncology compounds showed prevalent use of Child-Pugh classification for dedicated HI studies in noncancer subjects. NCIc is commonly used in cancer patient studies. NCIc tended to classify subjects as less impaired versus Child-Pugh (64.9%, 73.7%, and 61.5% of subjects with mild, moderate, and severe HI, respectively, via Child-Pugh were classified as at least 1 category less impaired via NCIc). PK analyses by NCIc were consistent with Child-Pugh for sunitinib, dacomitinib, and palbociclib. For bosutinib, NCIc showed less impact of HI than Child-Pugh; an opposite trend was observed for axitinib. The impact of this considerable discordance between the 2 systems on dosing decisions bears consideration. When Child-Pugh is used for HI study enrollment, exploratory PK analyses based on NCIc should be conducted. Prescribers should attempt to use the same classification system in the product label for dosing decisions.
TL;DR: It is demonstrated that tucatinib inhibits OCT2‐ and MATE1/2‐K‐mediated tubular secretion of creatinine, which may manifest as mild SCr elevations that are not indicative of renal impairment.
Abstract: Tucatinib is a potent tyrosine kinase inhibitor selective for human epidermal growth factor receptor 2 (HER2) approved by the US Food and Drug Administration for the treatment of HER2-positive metastatic breast cancer and in development for other HER2-positive solid tumors. Modest, reversible serum creatinine (SCr) elevations have been observed in tucatinib clinical trials. SCr is conveyed by the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) and 2-K (MATE2-K) and can increase in the presence of inhibitors of these transporters. In vitro, tucatinib inhibited OCT2-, MATE1-, and MATE2-K-mediated transport of metformin, with IC50 values of 14.7, 0.340, and 0.135 µM, respectively. Tucatinib also inhibited OCT2- and MATE1-mediated transport of creatinine, with IC50 values of 0.107 and 0.0855 µM, respectively. A phase 1 study with metformin administered orally in the absence and presence of tucatinib was conducted in 18 healthy subjects. Renal function was assessed by measuring glomerular filtration rate (GFR; based on iohexol plasma clearance) and endogenous markers (SCr, cystatin C-based estimated glomerular filtration rate [eGFR]) with and without tucatinib. Metformin exposure increased (1.4-fold) and renal clearance decreased (29.99-17.64 L/h) with tucatinib, with no effect on metformin maximum concentration. Creatinine clearance transiently decreased 23% with tucatinib. GFR and eGFR, which are unaffected by OCT2 and/or MATE1/2-K transport, were unchanged with tucatinib. These data demonstrate that tucatinib inhibits OCT2- and MATE1/2-K-mediated tubular secretion of creatinine, which may manifest as mild SCr elevations that are not indicative of renal impairment.
TL;DR: A physiologically based pharmacokinetic (PBPK) model was developed using mass balance and bioavailability data from adults and qualified using clinically observed data and can be useful for estimating the effects of impaired drug clearance on rivaroxaban pharmacokinetics.
Abstract: The non-vitamin K antagonist oral anticoagulant, rivaroxaban, is used in several thromboembolic disorders. Rivaroxaban is eliminated via both metabolic degradation and renal elimination as unchanged drug. Therefore, renal and hepatic impairment may reduce rivaroxaban clearance, and medications inhibiting these clearance pathways could lead to drug-drug interactions. This physiologically-based pharmacokinetic (PBPK) study investigated the pharmacokinetic behavior of rivaroxaban in clinical situations where drug clearance is impaired. A PBPK model was developed using mass balance and bioavailability data from adults and qualified using clinically observed data. Renal and hepatic impairment were simulated by adjusting disease-specific parameters and concomitant drug use was simulated by varying enzyme activity in virtual populations (n = 1000) and compared with pharmacokinetic predictions in virtual healthy populations and clinical observations. Rivaroxaban doses of 10 mg or 20 mg were used. Mild-to-moderate renal impairment had a minor effect on area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) of rivaroxaban, whereas severe renal impairment caused a more pronounced increase in these parameters versus normal renal function. AUC and Cmax increased with severity of hepatic impairment. These effects were smaller in the simulations compared with clinical observations. AUC and Cmax increased with the strength of cytochrome P450 3A4 and P-glycoprotein inhibitors in simulations and clinical observations. This PBPK model can be useful for estimating the effects of impaired drug clearance on rivaroxaban pharmacokinetics. Identifying other factors that affect the pharmacokinetics of rivaroxaban could facilitate the development of models that approximate real-world pharmacokinetics more accurately. This article is protected by copyright. All rights reserved.
TL;DR: The opportunistic sampling approach is a powerful and feasible method to obtain sufficient samples to study the variability of drug concentrations and protein binding for future pharmacokinetic studies in the pediatric critical care population.
Abstract: There has been increasing interest in incorporating β-lactam precision dosing into routine clinical care, but robust population pharmacokinetic models in critically ill children are needed for these purposes. The objective of this study was to demonstrate the feasibility of an opportunistic sampling approach that utilizes scavenged residual blood for future pharmacokinetic studies of cefepime, meropenem, and piperacillin. We aimed to show that opportunistic samples would cover the full concentration-versus-time profiles and to evaluate stability of the antibiotics in whole blood and plasma to optimize future use of the opportunistic sampling approach. A prospective observational study was conducted in a single-center pediatric intensive care unit, where pediatric patients administered at least 1 dose of cefepime, meropenem, or piperacillin/tazobactam and who had residual blood scavenged from samples obtained for routine clinical care were enrolled. A total of 138 samples from 22 pediatric patients were collected in a 2-week period. For all 3 antibiotics, the samples collected covered the entire dosing intervals and were not clustered around specific times. There was high variability in the free concentrations and in the percentage of drug bound to protein. There was less than 15% degradation for meropenem or piperacillin when stored in whole blood or plasma at 4°C after 6 days. Cefepime degraded by more than 15% after 3 days. The opportunistic sampling approach is a powerful and feasible method to obtain sufficient samples to study the variability of drug concentrations and protein binding for future pharmacokinetic studies in the pediatric critical care population.
TL;DR: These population PK models adequately described the plasma and ELF concentrations of ceftolozane and tazobactam, thus providing a foundation for further modeling and simulation, including the probability of target attainment assessments to support dose recommendations of C/T in adult patients with NP.
Abstract: Ceftolozane/tazobactam (C/T) is a combination of a novel cephalosporin with tazobactam, recently approved for the treatment of hospital-acquired and ventilator-associated pneumonia. The plasma pharmacokinetics (PK) of a 3-g dose of C/T (2 g ceftolozane and 1 g tazobactam) administered via a 1-hour infusion every 8 hours in adult patients with nosocomial pneumonia (NP) were evaluated in a phase 3 study (ASPECT-NP; NCT02070757). The present work describes the development of population PK models for ceftolozane and tazobactam in plasma and pulmonary epithelial lining fluid (ELF). The concentration-time profiles of both agents were well characterized by 2-compartment models with zero-order input and first-order elimination. Consistent with the elimination pathway, renal function estimated by creatinine clearance significantly affected the clearance of ceftolozane and tazobactam. The central volumes of distribution for both agents and the peripheral volume of distribution for tazobactam were approximately 2-fold higher in patients with pneumonia compared with healthy participants. A hypothetical link model was developed to describe ceftolozane and tazobactam disposition in ELF in healthy participants and patients with pneumonia. Influx (from plasma to the ELF compartment) and elimination (from the ELF compartment) rate constants were approximately 97% lower for ceftolozane and 52% lower for tazobactam in patients with pneumonia versus healthy participants. These population PK models adequately described the plasma and ELF concentrations of ceftolozane and tazobactam, thus providing a foundation for further modeling and simulation, including the probability of target attainment assessments to support dose recommendations of C/T in adult patients with NP.
TL;DR: In this article, the authors identify medications associated with altered disease outcomes in COVID-19 patients and identify the most commonly prescribed medications in a cohort of adults with COVID19.
Abstract: The interaction of COVID-19 with the majority of common prescriptions is broadly unknown. The purpose of this study is to identify medications associated with altered disease outcomes in COVID-19. A retrospective cohort comprised of all adult inpatient admissions to our centre with COVID-19 was analysed. Data concerning all antecedent prescriptions were collected and agents brought forward for analysis if prescribed to at least 20 patients in our cohort. Forty-two medications and 22 classes of medication were examined. Groups were propensity score matched and analysed by logistic and linear regression. The majority of medications did not show a statistically significant relationship with altered disease outcomes. Lower mortality was associated with use of pregabalin (p = 0.049, HR = 0.10 [0.01-0.92]), inhalers of any type (p = 0.015, HR = 0.33 [0.14-0.80]) and specifically beclomethasone (p = 0.032, HR = 0.10 [0.01-0.82]), tiotropium (p = 0.035, HR = 0.07 [0.01-0.83]) and steroid containing inhalers (p = 0.013, HR = 0.35 [0.15-0.79]). Gliclazide (p = 0.020, HR = 4.37 [1.26-15.18]) and proton pump inhibitor (p = 0.028, HR = 1.72 [1.06-2.79]) use was associated with greater mortality. Diuretic (p = 0.002, HR = 0.07 [0.01-0.37]) and statin (p = 0.006, HR = 0.35 [0.17-0.73]) use was associated with lower rates of critical care admission. Our data lends confidence to observing usual practice in COVID-19 patients by continuing antecedent prescriptions in the absence of an alternative acute contraindication. We highlight potential benefits in investigation of diuretics, inhalers, pregabalin and statins as therapeutic agents for COVID-19 and support further assessment of the safety of gliclazide and PPIs in the acute illness. This article is protected by copyright. All rights reserved.
TL;DR: The use environment of both natural and synthetic cannabinoids is described in this article, where the authors provide a summary of approved uses and an overview of mechanisms of action for adverse drug events with synthetic and natural cannabinoids.
Abstract: The purpose of this narrative review is to describe the current use environment of both natural and synthetic cannabinoids while providing context for cannabinoid chemistry and pharmacology. In addition to a long history of recreational and nonmedical use, natural cannabinoids are increasingly used as prescription products, through medical cannabis programs, and as consumer health products. Despite anecdotal safety evidence, cannabis and cannabinoids are pharmacologically complex and pose risks for adverse drug events and drug-drug interactions. Synthetic cannabinoids, particularly agonists of cannabinoid receptors, are more potent than natural cannabinoids and can lead to more severe reactions and medical emergencies. This review provides a summary of approved uses and an overview of mechanisms of action for adverse drug events with natural and synthetic cannabinoids. Clinical considerations for special populations that may be at heightened risk for drug-drug interactions and adverse drug events while using natural or synthetic cannabinoids are examined, and recommendations are provided.
TL;DR: A questionnaire-based study to assess the severity of COVID-19 in patients suffering PD andmultiple sclerosis, finding that none of them developed severe clinical manifestations of infectious disease, and suggested that this finding may reflect possible effect of amantadine antiviral activity against SARS-CoV2.
Abstract: Shortly after the onset of the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), concerns were raised about the potentially heightened risks of coronavirus disease 2019 (COVID-19) in patients with Parkinson disease (PD).1 To substantiate these suspicions, we performed a questionnaire-based study to assess the severity of COVID-19 in patients suffering PD andmultiple sclerosis (MS), whose SARSCoV-2 infection was confirmed by reverse transcriptase polymerase chain reaction of nasopharyngeal swabs. We found that none of them (PD, n= 5;MS, n= 10) developed severe clinical manifestations of infectious disease. Importantly, all patients were taking amantadine.2 Although the aforementioned lack of severe cases among patients taking amantadine could happen by chance, it also provoked hypothesis generation. We suggested that our finding may reflect possible effect of amantadine antiviral activity against SARS-CoV2. Indeed, it has recently been shown that amantadine interferes with the lysosomal milieu andmay inhibit the virus’s entry to host cells.3 However, currently amantadine is the foremost neurological drug, used to treat PD and disorders of consciousness and prescribed off-label to patients suffering from MS. The drug enters the blood-brain barrier and acts as a weak but unique glutamate/N-methyl-Daspartate receptor antagonist, which concomitantly activates the cystine/glutamate antiporter and stimulates glutathione synthesis.4 We would like to point to 2 other possible mechanisms by which this drug could contribute to mitigation of COVID-19 in infected patients. The first relates to the anti-fatigue effect. Fatigue, a very prevalent symptom in MS (>90% patients), is a multifaceted phenomenon partially related to central mechanisms. Already >3 decades ago a serendipitous observation was made that a patient with MS had a remarkable improvement in fatigue while taking amantadine to prevent influenza, and the effect was soon confirmed in a small double-blind controlled study. Amantadine is the only drug that seemed to improve fatigue symptoms in MS, although the data were limited,5 and a more recent study did not support such conclusion.6 Fatigue is one of the most prevalent symptoms of COVID-19 in adults and is more common in patients who require hospitalization. A recent report evidenced that COVID-19 increased fatigue in a cohort of patients with PD.7 Importantly, patients with MS and PD display blunted respiratory response to hypercapina and hypoxia.8,9 A connection of depressed responsivity to carbon dioxide and hypoxia with fatigue appears intuitively highly probable. The second mechanism by which amantadine may benefit patients with COVID-19 relates to its arousalenhancing effect. Impaired consciousness is a frequent central nervous system manifestation of COVID-19. Since arousal is a normal, physiological response to respiratory stimuli such as hypoxia and hypercapnia, it is plausible to expect that impaired consciousness in patients with COVID-19 blunt their respiratory response to hypoxia and hypercapnia. Depressed response to hypercapnia and hypoxia may be an important factor in the development of severe forms of COVID-19, including the so-called silent, or “happy” hypoxemia, a phenomenon of the absence of dyspnea in patients with COVID-19 who exhibit severe hypoxemia with considerable risk of death.10 Although it is too early to advocate amantadine as a treatment for COVID-19, a controlled trial of this drug for postexposure prophylaxis of SARS-CoV2 infection is indicated.
TL;DR: The model‐based simulations described indicate that every‐5‐week or every‐6‐week dosing is likely to maintain the efficacy of natalizumab, particularly at body weights <80 kg, in patients who switch after a period of stability on every‐4‐ week dosing, as well as decreasing as dosing intervals and body weight increase.
Abstract: Natalizumab is approved for multiple sclerosis treatment at a dose of 300 mg every 4 weeks. Extended-interval dosing of natalizumab has been proposed as a strategy to mitigate the risk of progressive multifocal leukoencephalopathy, but the efficacy of extended-interval dosing is not established. Previous models suggesting lower efficacy when initiating natalizumab treatment with extended-interval dosing rather than every-4-week dosing are inconsistent with reports from clinical observations and real-world studies conducted in patient populations switching to extended-interval dosing after a period of receiving natalizumab every 4 weeks. Here, the efficacy of natalizumab extended-interval dosing was modeled specifically in patients switching from every-4-week dosing to extended-interval dosing. Published population pharmacokinetic/pharmacodynamic models were used to simulate the distribution of alpha-4 integrin saturations for different body weight categories and dosing intervals (every 5, 6, 7, 8, 10, or 12 weeks). Generalized estimating equations relating alpha-4 integrin saturation to probability of multiple sclerosis lesion or relapse were derived from RESTORE trial data, which included patients (n = 175) who discontinued natalizumab after being treated every 4 weeks for ≥1 year and had no relapses in the year before discontinuation. The model-based simulations described indicate that every-5-week or every-6-week dosing is likely to maintain the efficacy of natalizumab, particularly at body weights <80 kg, in patients who switch after a period of stability on every-4-week dosing. The efficacy of natalizumab decreases as dosing intervals and body weight increase. Partial model validation was achieved in that observed outcomes in an independent clinical study were similar to those predicted by the models.
TL;DR: Despite differences in PK, the onset of the decrease in CRP and ANC after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab, and effects and safety were consistent with previous studies.
Abstract: We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin-6 (IL-6), soluble IL-6 receptor, and C-reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single-dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target-mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7-15 days for CRP and 3-5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies.
TL;DR: The relationship between ribociclib and absolute neutrophil count (ANC) was characterized in patients with cancer using population pharmacokinetics (popPK) and pharmacokinetic/pharmacodynamic (PK/PD).
Abstract: The population pharmacokinetics (popPK) of ribociclib and population pharmacokinetic/pharmacodynamic (PK/PD) relationship between ribociclib and absolute neutrophil count (ANC) were characterized in patients with cancer. PopPK and ANC PK/PD modeling were both conducted in 2 rounds per data availability. Initial models were developed based on data sets from early-phase trials and qualified using external data from the phase III MONALEESA-2 trial. The second round of analyses was performed using updated data sets that included 2 more phase III trials (MONALEESA-3 and -7). The popPK and ANC PK/PD models adequately described the data and demonstrated reasonable predictive ability. Covariate analysis showed that ribociclib PK were not affected by age, sex, race, baseline Eastern Cooperative Oncology Group (ECOG) status (grade 1), mild/moderate renal impairment, mild hepatic impairment, or concomitant use of combination partners, including aromatase inhibitors (letrozole, anastrozole) or fulvestrant, proton-pump inhibitors, or weak cytochrome P450 3A4/5 inhibitors. Body weight had no impact on ribociclib clearance to warrant dose adjustment. The ANC PK/PD relationship was not affected by age, weight, sex, race, baseline ECOG status (grade 1), or concomitant use of letrozole, anastrozole, or fulvestrant. The PK/PD analysis confirmed reversibility of ribociclib's effect on ANC; it also suggested that lowering the dose of ribociclib would mitigate ANC decrease and neutropenia risk. The popPK and ANC PK/PD analyses support the use of ribociclib in combination with an aromatase inhibitor or fulvestrant in patients with hormone receptor–positive, human epidermal growth factor receptor-2–negative advanced or metastatic breast cancer without dose adjustment in subpopulations, and the use of dose interruption/reduction to mitigate potential treatment-emergent neutropenia.
TL;DR: In this article, the authors summarize the accumulated knowledge from 53 approved new drug applications submitted to the Office of Clinical Pharmacology, US Food and Drug Administration, from 2016 to 2018 that contained physiologically based pharmacokinetic (PBPK) models to understand how in vitro data are used in PBPK models to assess drug metabolism and predict DDIs.
Abstract: The key parameters necessary to predict drug-drug interactions (DDIs) are intrinsic clearance (CLint ) and fractional contribution of the metabolizing enzyme toward total metabolism (fm ). Herein, we summarize the accumulated knowledge from 53 approved new drug applications submitted to the Office of Clinical Pharmacology, US Food and Drug Administration, from 2016 to 2018 that contained physiologically based pharmacokinetic (PBPK) models to understand how in vitro data are used in PBPK models to assess drug metabolism and predict DDIs. For evaluation of CLint and fm , 29 and 20 new drug applications were included for evaluation, respectively. For CLint , 86.2% of the PBPK models used modified values based on in vivo data with modifications ranging from -82.5% to 2752.5%. For fm , 45.0% of the models used modified values with modifications ranging from -28% to 178.6%. When values for CLint were used from in vitro testing without modification, the model resulted in up to a 14.3-fold overprediction of the area under the concentration-time curve of the substrate. When values for fm from in vitro testing were used directly, the model resulted in up to a 2.9-fold underprediction of its DDI magnitude with an inducer, and up to a 1.7-fold overprediction of its DDI magnitude with an inhibitor. Our analyses suggested that the in vitro system usually provides a reasonable estimation of fm when the drug metabolism by a given CYP pathway is more than 70% of the total clearance. In vitro experiments provide important information about basic PK properties of new drugs and can serve as a starting point for building a PBPK model. However, key PBPK parameters such as CLint and fm still need to be optimized based on in vivo data.
TL;DR: A review of the epidemiology and pharmacology of gabapentinoids relevant to their emerging misuse potential and guidance for clinical and regulatory management is provided in this article, where the authors identify higher rates of misuse in the United States, likely because of greater availability and less regulated prescribing.
Abstract: This article will review the epidemiology and pharmacology of gabapentinoids (gabapentin and pregabalin) relevant to their emerging misuse potential and provide guidance for clinical and regulatory management. Gabapentinoids are γ-aminobutyric acid analogues that produce their therapeutic effects by inhibiting voltage-gated calcium channels and decreasing neurotransmitter release. Recently gabapentinoid prescribing and use have increased tremendously. Although traditionally thought to possess a favorable safety profile, gabapentinoid misuse has also risen significantly. Gabapentinoid misuse generally occurs in combination with other substances, most notably opioids, and may be for purposes of eliciting euphoric effects, enhancing the effects of other substances, or self-treating conditions such as withdrawal, pain, anxiety, or insomnia. Given its faster onset, increased bioavailability and potency, and nonsaturable absorption, pregabalin's pharmacokinetics theoretically enhance its misuse liability versus gabapentin. However, gabapentin can produce similar euphoric effects, and epidemiologic studies have identified higher rates of gabapentin misuse in the United States, likely because of greater availability and less regulated prescribing. Although adverse events of gabapentinoid-only ingestion are relatively benign, a growing body of evidence indicates that gabapentinoids significantly increase opioid-related morbidity and mortality when used concomitantly. In addition, significant withdrawal effects may occur on abrupt discontinuation. As a result of these trends, several US states have begun to further regulate gabapentinoid prescribing, reclassifying it as a controlled substance or mandating reporting to local prescription drug-monitoring programs. Although increased regulation of gabapentin prescribing may be warranted, harm reduction efforts and increased patient and provider education are necessary to mitigate this concerning gabapentinoid misuse trend.
TL;DR: In this paper, the optimal dosing of isoniazid (INH) for each NAT2 acetyltransferase 2 (NAT2) phenotype with respect to the probability of achieving a pharmacokinetic (PK)/pharmacodynamic target was provided.
Abstract: The wide variability of isoniazid (INH) pharmacokinetics is mainly attributed to the trimodal N-acetyltransferase 2 (NAT2) acetylator phenotype, i.e., rapid, intermediate, and slow. Consequently, a uniform INH dose in the current clinical practice may lead to treatment failure and drug resistance emergence. There is a lack of studies on specific doses of INH for different NAT2 acetylator phenotypes among tuberculosis patients. Therefore, we aimed to provide insight into the optimal dosing of INH for each NAT2 acetylator phenotype with respect to the probability of achieving a pharmacokinetic (PK)/pharmacodynamic target. PK, NAT2 genotype, and clinical data were collected in a multicenter prospective cohort study conducted at 13 clinical centers in Korea. Population PK modeling and simulation were carried out. Data from 454 TB patients were divided into a training dataset and a test dataset with a ratio of 4 to 1. The PK of the training data were best described by a two-compartment model with allometric scaling for the body size effect. Importantly, NAT2 acetylator phenotypes significantly affected the apparent clearance. Our model provided better predictive performance compared to previously published models, which was evaluated by external validation using the test set. The simulation for assessing the target efficacy and toxicity indicated that the best INH dosing regimens for Korean tuberculosis patients were once-daily doses of 400, 300, and 200 mg for rapid, intermediate, and slow acetylators, respectively. In conclusion, our study provides a step forward in precision dosing for anti-tuberculosis management. This article is protected by copyright. All rights reserved.
TL;DR: The prostatic population pharmacokinetic model, which included a covariate analysis, adequately predicted prostate tissue concentrations in the patient population, and provides helpful recommendations for the treatment of bacterial prostatitis and preoperative prophylaxis in prostatectomy.
Abstract: This study aims to define the penetration of ampicillin and sulbactam into prostate tissue, develop a prostatic pharmacokinetic model of each drug, and assess the appropriateness of ampicillin-sulbactam regimens for the treatment of prostatitis and the prophylaxis of postoperative infection, based on a pharmacokinetic and pharmacodynamic simulation. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-hour infusion of 1.5 g (1:0.5 g) or 3 g (2:1 g) ampicillin-sulbactam before transurethral resection of the prostate. Ampicillin and sulbactam concentrations in plasma and prostate tissue were measured. The prostate tissue/plasma ratios of both ampicillin and sulbactam were approximately 0.37 (area under the drug concentration-time curve), and penetration was similar. The prostatic population pharmacokinetic model, which included a covariate analysis, adequately predicted prostate tissue concentrations in our patient population. For therapeutic use, aiming for a bactericidal target of 50% of time above minimum inhibitory concentration (T > MIC) in prostate tissue, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability against only Enterococcus faecalis in typical patients with a creatinine clearance (CLcr ) of 30 mL/min. For prophylactic use, aiming for a bacteriostatic target of 30% T > MIC, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability of attaining the bacteriostatic target against E. faecalis and Proteus species when CLcr was 30 mL/min. Based on prostatic simulations, the present study provides helpful recommendations for the treatment of bacterial prostatitis and preoperative prophylaxis in prostatectomy.
TL;DR: In this article, the effects of lidocaine and (R,S)-ketamine infusions were compared in 6 patients with refractory chronic migraine, and metabolite analysis was performed to determine its metabolic profile in this population.
Abstract: Patients with refractory chronic migraine have substantial disability and have failed many acute and preventive medications. When aggressive intravenous therapy is indicated, both lidocaine and (R,S)-ketamine infusions have been used successfully to provide relief. Retrospective studies have shown that both agents may be associated with short-term analgesia. In this prospective, observational pilot study of 6 patients, we compared the effects of lidocaine and (R,S)-ketamine infusions and performed metabolite analyses of (R,S)-ketamine to determine its metabolic profile in this population. One of (R,S)-ketamine's metabolites, (2R,6R)-hydroxynorketamine, has been shown in animal studies to reduce pain, but human studies in patients undergoing continuous (R,S)-ketamine infusions for migraine are lacking. All 6 patients tolerated both infusions well with mild adverse effects. The baseline mean pain rating (0-10 numeric rating scale) decreased from 7.5 ± 2.2 to 4.7 ± 2.8 by end of lidocaine treatment ( P ≤ . 05 ) but increased to 7.0 ± 1.4 by the postdischarge visit at 4 weeks (P > .05 vs baseline). The baseline mean pain rating prior to ketamine treatment was 7.4 ± 1.4, which decreased to 3.7 ± 2.3 by the end of the hospitalization ( P ≤ . 05 ) but increased to 7.2 ± 1.7 by the postdischarge visit at 6 weeks (P > .05 vs baseline). For the primary outcome the change in pain from baseline to end of treatment was greater for ketamine than lidocaine (-3.7 vs -2.8; P ≤ . 05 ), but this has minimal clinical significance. Ketamine metabolite analysis revealed that (2R,6R)-hydroxynorketamine was the predominant metabolite during most of the infusion, consistent with previous studies.