Showing papers in "The Journal of Clinical Pharmacology in 2005"

Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use.

Abstract: Danshen, the dried root of Salvia miltiorrhiza, has been widely used in China and, to a lesser extent, in Japan, the United States, and other European countries for the treatment of cardiovascular and cerebrovascular diseases. In China, the specific clinical use is angina pectoris, hyperlipidemia, and acute ischemic stroke. The current review covers its traditional uses, chemical constituents, pharmacological activities, pharmacokinetics, clinical applications, and potential herb-drug interactions based on information obtained in both the English and Chinese literature. Although numerous clinical trials have demonstrated that certain Danshen products in China are effective and safe for the treatment of cardiovascular diseases, most of these lack sufficient quality. Therefore, large randomized clinical trials and further scientific research to determine its mechanism of actions will be necessary to ensure the safety, effectiveness, and better understanding of its action.

Multiple Drug Resistance in Cancer Revisited: The Cancer Stem Cell Hypothesis

Abstract: The failure to eradicate cancer may be as fundamental as a misidentification of the target. Current therapies succeed at eliminating bulky disease but often miss a tumor reservoir that is the source of disease recurrence and metastasis. Recent advances in the understanding of tissue development and repair cause us to revisit the process of drug resistance as it applies to oncogenesis and tumor heterogeneity. The cancer stem cell hypothesis states that the cancer-initiating cell is a transformed tissue stem cell, which retains the essential property of self-protection through the activity of multiple drug resistance (MDR) transporters. This resting constitutively drug-resistant cell remains at low frequency among a heterogeneous tumor mass. In the context of this hypothesis, the authors review the discovery of MDR transporters in cancer and normal stem cells and the failure of MDR reversal agents to increase the therapeutic index of substrate antineoplastic agents.

Origin and Uses of Primum Non Nocere—Above All, Do No Harm!

Abstract: The so-called Hippocratic injunction to do no harm has been an axiom central to clinical pharmacology and to the education of medical and graduate students. With the recent reexamination of the nature and magnitude of adverse reactions to drugs, the purposes of this research and review were to discover the origin of this unique Latin expression. It has been reported that the author was neither Hippocrates nor Galen. Searches of writings back to the Middle Ages have uncovered the appearance of the axiom as expressed in English, coupled with its unique Latin, in 1860, with attribution to the English physician, Thomas Sydenham. Commonly used in the late 1800s into the early decades of the 1900s, it was nearly exclusively transmitted orally; it rarely appeared in print in the early 20th century. Its applicability and limitations as a guide to the ethical practice of medicine and pharmacological research are discussed. Despite insufficiencies, it remains a potent reminder that every medical and pharmacological decision carries the potential for harm.

Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement.

Abstract: Dabigatran etexilate is an oral low-molecular-weight direct thrombin inhibitor Following oral administration, dabigatran etexilate is rapidly converted to its active form, dabigatran The authors investigated the absorption, distribution, and elimination of a single 150-mg dose capsule formulation of dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement In an open-label, 3-way crossover study, dabigatran etexilate was administered to 18 male volunteers in the fasted state, after administration of food and with coadministration of the proton pump inhibitor, pantoprazole In a subsequent multicenter, open-label study, 59 patients received a single dose of dabigatran etexilate, administered 1 to 3 hours following total hip replacement In healthy volunteers, food had no effect on the extent of absorption of dabigatran etexilate, although there was reduced interindividual variability for dabigatran maximum plasma concentration and AUC(0-infinity) A decrease in the mean dabigatran AUC(0-infinity) (904 to 705 ng*h/mL) occurred with coadministration of pantoprazole In patients undergoing total hip replacement, immediate onset of absorption was seen with the maximum plasma concentration of dabigatran occurring after 6 hours The AUC(0-24) of dabigatran was 88% of the steady-state AUC using a preliminary tablet formulation and 106% of that seen in the healthy volunteer study Compared with healthy volunteers, the postoperative profile was flattened with delayed peak concentrations In summary, administration of the dabigatran etexilate capsule with food has no effect on the extent of dabigatran absorption, with a moderate decrease when coadministered with pantoprazole Adequate plasma concentrations of dabigatran were seen with early postoperative administration of the dabigatran etexilate capsule These pharmacokinetic characteristics confirm the suitability of this oral solid dosage form for use in future clinical trials

Interaction of Warfarin With Drugs, Natural Substances, and Foods

Abstract: Variability in the anticoagulant response to warfarin is an ongoing clinical dilemma. Fluctuations in dietary vitamin K are an important source of variance, and the need for constancy in vitamin K intake is routinely emphasized for warfarin-treated patients. Anticoagulant response is also influenced by a number of drugs that induce or inhibit warfarin metabolism, as well as by genetic polymorphisms that may modulate expression or activity of CYP2C9, the isoform mediating clearance of S-warfarin. The possible role of dietary factors other than vitamin K, as well as of herbal medicines or supplements as contributors to the instability of anticoagulation in warfarin-treated patients, has received recent attention. St. John's wort and possibly some ginseng formulations may have the potential to diminish warfarin anticoagulation, apparently by inducing CYP2C9 activity. Otherwise, there is no reliable evidence to indicate that any dietary component (other than vitamin K) or any herbal product has an effect on the anticoagulant response to warfarin. Scientific conclusions on this important therapeutic issue should be based on valid scientific data rather than unvalidated case reports.

Population Pharmacokinetics of Rituximab (Anti‐CD20 Monoclonal Antibody) in Rheumatoid Arthritis Patients During a Phase II Clinical Trial

Abstract: Rituximab is a B cell-depleting anti-CD20 chimeric IgGkappa monoclonal antibody being investigated for the treatment of rheumatoid arthritis. The purpose of this study was to develop a population pharmacokinetic model in rheumatoid arthritis patients. In addition, the final pharmacokinetic model was used to assess the variability in drug exposure (AUC0-infinity) for fixed versus body surface area-based dosing. A total of 102 patients were included in this population pharmacokinetic analysis. A 2-compartment pharmacokinetic model described the data reasonably well. Body surface area and gender were the most significant covariates for both CL and Vc. Body surface area alone only explained about 19.7% of the total interindividual variability of CL. In a simulation study, body surface area-based dosing normalized drug exposure over a wide range of body surface area but did not seem to improve the predictability of rituximab AUC0-infinity in rheumatoid arthritis patients. Therefore, no rationale for body surface area-based dosing for rituximab in rheumatoid arthritis patients was found.

Examination of 209 Drugs for Inhibition of Cytochrome P450 2C8

Abstract: Cytochrome P450 2C8 is involved in the metabolism of drugs such as paclitaxel, repaglinide, rosiglitazone, and cerivastatin, among others. An in vitro assessment of 209 frequently prescribed drugs and related xenobiotics was carried out to examine their potential to inhibit CYP2C8. A validated sensitive, moderate-throughput high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) assay was used to detect N-desethylamodiaquine, the CYP2C8-derived major metabolite of amodiaquine metabolism, using heterologously expressed recombinant CYP2C8 (rhCYP2C8) and pooled human liver microsomes. The 209 drugs were first tested at 30 μM for their ability to inhibit rhCYP2C8. Forty-eight compounds exhibited greater than 50% inhibition and were further evaluated for measurement of IC 5 0 . The six most potent inhibitors (IC 5 0 <1 μM) from this set were measured for IC 5 0 in pooled human liver microsomes, and the most potent inhibitor identified was the leukotriene receptor antagonist, montelukast (IC 5 0 = 19.6 nM). Inhibitors of CYP2C8 were identified from a wide variety of therapeutic classes, with no single class predominating. Other potent inhibitors included candesartan cilexetil (cyclohexylcarbonate ester prodrug of candesartan), zafirlukast, clotrimazole, felodipine, and mometasone furoate. Seventeen moderate inhibitors of rhCYP2C8 (1 < IC 5 0 < 10 μM) included salmeterol, raloxifene, fenofibrate, ritonavir, levothyroxine, tamoxifen, loratadine, quercetin, oxybutynin, medroxyprogesterone, simvastatin, ketoconazole, ethinyl estradiol, spironolactone, lovastatin, nifedipine, and irbesartan. These in vitro data were used along with clinical pharmacokinetic information in predicting potential drug-drug interactions that could occur by inhibition of CYP2C8. Although almost all drugs tested are not expected to cause drug interactions via inhibition of CYP2C8, montelukast was identified as being of concern as a potential inhibitor of clinical relevance. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which CYP2C8 is involved in metabolism and warrant investigation of the possibility of clinical drug interactions mediated by inhibition of this enzyme.

Pharmacokinetics of micafungin in healthy volunteers, volunteers with moderate liver disease, and volunteers with renal dysfunction.

Abstract: Micafungin is an antifungal agent metabolized by arylsulfatase with secondary metabolism by catechol-O-methyltransferase. The objectives of this study were to estimate the pharmacokinetic parameters and plasma protein binding of micafungin in volunteers with moderate hepatic dysfunction (n = 8), volunteers with creatinine clearance < 30 mL/min (n = 9), and matched controls (n = 8 and n = 9, respectively). Single-dose micafungin pharmacokinetics were estimated using noncompartmental techniques. There was a statistically lower area under the observed micafungin concentration-time curve (AUC) from time 0 to infinity for subjects with moderate hepatic dysfunction as compared to control subjects (97.5 +/- 19 microg.h/mL vs 125.9 +/- 26.4 microg.h/mL, P = .03), although there was no difference in micafungin weight-adjusted clearance (10.9 +/- 1.7 mL/h/kg vs 9.8 +/- 1.8 mL/h/kg, P = .2). The difference in area under the concentration-time curve may be explained by the differences in body weight between subjects and controls. Renal dysfunction did not alter micafungin pharmacokinetics.

Rheumatoid Arthritis: An Overview of New and Emerging Therapies

Abstract: Rheumatoid arthritis (RA) is a chronic, inflammatory, systemic autoimmune disorder characterized by symmetric inflammation of synovial joints leading to progressive erosion of cartilage and bone. The aim of treatment is to mitigate joint destruction, preserve function, and prevent disability. The American College of Rheumatology guidelines for the treatment of RA recommend that newly diagnosed patients with RA begin treatment with disease-modifying antirheumatic drugs (DMARDs) within 3 months of diagnosis. Methotrexate remains the most commonly prescribed DMARD and is the standard by which recent new and emerging therapies are measured. Increasing knowledge regarding the immunologic basis of RA and advances in biotechnology have resulted in new, targeted biological therapies against proinflammatory cytokines that have dramatically changed the treatment paradigm and outcomes of patients with RA. This article reviews the pharmacological rationale underlying RA therapy, with a focus on currently available biological therapies and new therapies in development.

Pharmacokinetics of anthocyanins and ellagic acid in healthy volunteers fed freeze-dried black raspberries daily for 7 days.

Abstract: Eleven subjects completed a clinical trial to determine the safety/tolerability of freeze-dried black raspberries (BRB) and to measure, in plasma and urine, specific anthocyanins-cyanidin-3-glucoside, cyanidin-3-sambubioside, cyanidin-3-rutinoside, and cyanidin-3-xylosylrutinoside, as well as ellagic acid. Subjects were fed 45 g of freeze-dried BRB daily for 7 days. Blood samples were collected predose on days 1 and 7 and at 10 time points postdose. Urine was collected for 12 hours predose on days 1 and 7 and at three 4-hour intervals postdose. Maximum concentrations of anthocyanins and ellagic acid in plasma occurred at 1 to 2 hours, and maximum quantities in urine appeared from 0 to 4 hours. Overall, less than 1% of these compounds were absorbed and excreted in urine. None of the pharmacokinetic parameters changed significantly between days 1 and 7. In conclusion, 45 g of freeze-dried BRB daily are well tolerated and result in quantifiable anthocyanins and ellagic acid in plasma and urine.

The clinical pharmacokinetics of phosphodiesterase-5 inhibitors for erectile dysfunction.

Abstract: Differences in the clinical pharmacology of the 3 currently available oral phosphodiesterase-5 (PDE5) inhibitors, sildenafil, vardenafil, and tadalafil, are largely determined by their clinical pharmacokinetics as well as their PDE inhibitory activity profile. This review comparatively discusses the major characteristics of the pharmacokinetic profile of all 3 PDE5 inhibitors, including bioavailability and rate of absorption, Biopharmaceutical Classification System categorization, elimination mechanisms, and metabolic profile including active metabolites, as well as the drug-drug interaction potential and modification of pharmacokinetic properties under selected physiologic and pathophysiologic conditions. The review is aimed at providing comparative clinical pharmacology data to allow for scientifically rational, evidence-based prescribing and dosing decisions regarding the clinical use of these medications for the treatment of erectile dysfunction.

Clinical Pharmacology of Rasagiline: A Novel, Second-Generation Propargylamine for the Treatment of Parkinson Disease

Abstract: Rasagiline is a novel second-generation propargylamine that irreversibly and selectively inhibits monoamine oxidase type B (MAO-B). For the management of Parkinson disease (PD), rasagiline is efficacious across the span of PD stages ranging from monotherapy in early disease to adjunctive treatment in patients with advancing disease and motor fluctuations. Rasagiline completely and selectively inhibits MAO-B with a potency 5 to 10 times greater than selegiline. Unlike the prototype propargylamine selegiline, which is metabolized to amphetamine derivatives, rasagiline is biotransformed to aminoindan, a non-amphetamine compound. Rasagiline is well tolerated with infrequent cardiovascular or psychiatric side effects, and at the recommended therapeutic dose of up to 1 mg once daily, tyramine restriction is unnecessary. In addition to MAO-B inhibition, the propargylamine chain also confers dose-related antioxidant and antiapoptotic effects, which have been associated with neuroprotection in multiple experimental models. Thus, in addition to symptomatic benefits, rasagiline offers the promise of clinically relevant neuroprotection.

Bioavailability of azacitidine subcutaneous versus intravenous in patients with the myelodysplastic syndromes.

Abstract: The primary objectives of this study were to characterize the absolute bioavailability of azacitidine after subcutaneous (SC) administration and to compare the single-dose pharmacokinetics of azacitidine following SC and intravenous (IV) administration. Six patients with myelodysplastic syndromes were randomly assigned according to a crossover design to treatment A, consisting of azacitidine administered as a single 75-mg/m(2) SC dose, or treatment B, consisting of azacitidine administered as a single 75-mg/m(2) IV infusion dose over 10 minutes. A minimum of 7 days and a maximum of 28 days were permitted between treatments. The study demonstrated good bioavailability of a SC azacitidine dose compared to an IV infusion treatment. The exposure profiles following SC drug administration illustrate measurable azacitidine levels with bioavailability (AUC) values within 89% of those measured following IV administration (range, 70%-112%). The median IV half-life was 0.36 +/- 0.02 hours compared to 0.69 +/- 0.14 hours for SC administration. Regardless of the route of administration, a single dose of azacitidine, 75 mg/m(2), was generally well tolerated.

The pharmacokinetics of escitalopram after oral and intravenous administration of single and multiple doses to healthy subjects.

Abstract: The pharmacokinetics of escitalopram (S-citalopram) and its principal metabolite, S-demethylcitalopram (S-DCT), were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion of escitalopram, the mean systemic clearance and volume of distribution were 31 L/h and 1,100 L, respectively. After oral administration of single or multiple doses, the absorption was relatively fast, with the maximum observed plasma or serum concentration (C(max)) attained after 3 to 4 hours. The mean half-lives were 27 and 33 hours, respectively; steady state was attained within 10 days. The area under the plasma or serum concentration time curve from time zero to 24 hours and C(max) was both linear and proportional to the dose. The apparent volume of distribution was around 20 L/kg. Comparison of the systemic and oral clearance implied a high absolute bioavailability. There was no evidence of interconversion from S-citalopram to R-citalopram either in plasma or in urine. Concurrent intake of food had no effect on the pharmacokinetics of escitalopram or its metabolite. All treatments were well tolerated.

Posaconazole Pharmacokinetics, Safety, and Tolerability in Subjects With Varying Degrees of Chronic Renal Disease

Abstract: Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL(CR) = 50-80 mL/min), moderate (CL(CR) = 20-49 mL/min), and severe chronic renal disease (CL(CR) .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only approximately 3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (approximately 98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single-dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.

Long-acting octreotide and prolonged-release lanreotide formulations have different pharmacokinetic profiles.

Abstract: Single-dose pharmacokinetic (PK) profiles and multiple-dose PK modeling were compared for long-acting octreotide (20 or 60 mg) and prolonged-release lanreotide (90 or 120 mg) over 91 days; steady-state profiles were simulated. All treatments were well tolerated. Octreotide 20-mg profile showed increased concentration on day 1, lag from days 2 to 6, then prolonged plateau phase (days 11-41); 60-mg PK was dose proportional. Lanreotide 90-mg profile showed C(max) on day 1 then elimination (apparent t1/2 25.5 days); 120-mg profile was underproportional. Steady-state PK of octreotide 20 mg/28 d suggested a C(mean) of 1216 rhog/mL (range, 1065-1585) with low fluctuation index (43%). Steady-state PK of lanreotide 90 mg/28 d suggested a C(mean) of 4455 rhog/mL (range, 2499-9279) with high fluctuation index (152%). Long-acting octreotide had more predictable PK than prolonged-release lanreotide. Simulated steady-state profiles suggest long-acting octreotide could be optimized to meet individual patient needs. In contrast, prolonged-release lanreotide requires exposure constantly above the therapeutic target to enable monthly long-term therapy.

Clinical Pharmacokinetics of Etanercept: A Fully Humanized Soluble Recombinant Tumor Necrosis Factor Receptor Fusion Protein

Abstract: Etanercept, a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein, is an approved treatment for rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and psoriasis. Etanercept is absorbed slowly from the site of subcutaneous injection, with time to peak concentration at approximately 48 to 60 hours, and is cleared slowly from the body with a t(1/2) of 70 to 100 hours. The absolute bioavailability of etanercept was 58% in healthy subjects following subcutaneous administration. The 25-mg twice-weekly dosage regimen generates systemic exposures comparable to 50 mg once weekly, as predicted by pharmacokinetic modeling and simulation and later confirmed by clinical studies. The pharmacokinetics of etanercept in patients with rheumatoid arthritis are comparable to those in healthy individuals and patients with ankylosing spondylitis, congestive heart failure, and psoriasis. In children with polyarticular-course juvenile rheumatoid arthritis, after subcutaneous doses of 0.4 mg/kg twice weekly, the clearance of etanercept may be slightly reduced in children aged 4 to 8 years. Pharmacokinetic simulation predicts that a dose of 0.8 mg/kg once weekly generates comparable systemic exposure as 0.4 mg/kg twice weekly. No requirement for etanercept dosage adjustment is needed when etanercept is coadministered with warfarin, digoxin, or methotrexate.

Tolerability, Gut Effects, and Pharmacokinetics of Methylnaltrexone Following Repeated Intravenous Administration in Humans

Abstract: Previous studies have shown that a single dose of methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid-induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid-induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple-dose regimen of methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, methylnaltrexone decreased oral-cecal transit time from a pretreatment baseline value of 101.3 +/- 29.4 min (mean +/- SD) to 82.5 +/- 20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538 +/- 237 and 675 +/- 180 ng/mL after doses 1 and 2, respectively. Based on 6-hour sampling periods, the plasma half-life, 2.5 +/- 0.5 and 2.9 +/- 0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of methylnaltrexone to these opioid-naive volunteers suggests that endogenous opioids modulate human gut motility.

Single-dose and steady-state pharmacokinetics of eslicarbazepine acetate (BIA 2-093) in healthy elderly and young subjects.

Abstract: slicarbazepine acetate (BIA 2-093, S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide) is a new drug currently in phase III forthetreatmentofepilepsyandphaseIIforbipolardisor-der. It is chemically related to carbamazepine andoxcarbazepine but has been specifically designed toavoid the production of toxic metabolites (such asepoxides) and to overcome enantiomeric impurity andthe unnecessary production of enantiomers ordiastereoisomers of metabolites and conjugates, with-out losing pharmacological activity.

Concomitant cyclosporine and micafungin pharmacokinetics in healthy volunteers.

Abstract: Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of CYP3A-mediated metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of cyclosporine and micafungin before and with concomitant administration. The pharmacokinetics of single-dose oral cyclosporine (5 mg/kg) were estimated on days 1, 9, and 15 (n = 27). Subjects received micafungin (100 mg/d over 1 hour) on days 7, 9, and 11 through 15. Micafungin pharmacokinetics were estimated on days 7, 9, and 15. Mean apparent oral cyclosporine clearances were estimated to be 645 ± 236 mL/h/kg, 546 ± 101 mL/h/kg (P = .01), and 540 ± 104 mL/h/kg (P = .02) for days 1, 9, and 15, respectively. Micafungin appears to be a mild inhibitor of cyclosporine metabolism.

The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects.

Abstract: Daptomycin pharmacokinetics were studied in adult volunteers who were moderately obese (body mass index [BMI] = 25-39.9 kg/m2) or morbidly obese (BMI > or =40 kg/m2) and a matched (gender, age, renal function) nonobese (BMI between 18.5 and 24.9 kg/m2) control group. All subjects received a dose of 4 mg/kg total body weight (TBW) by intravenous infusion (30 minutes). Daptomycin plasma half-life, the fraction of the dose excreted unchanged in urine, and daptomycin absolute renal clearance (mL/h) were unchanged as a function of obesity. The absolute volume of distribution (Vz and Vss) and plasma clearance (CL) for daptomycin were higher in obese subjects as compared to nonobese matched controls. The rate of change of Vz and CL with increasing BMI was greater when these pharmacokinetic parameters were expressed in absolute terms compared to when they were normalized for TBW or ideal body weight. This suggests that increases in body mass associated with obesity are proportionality higher than the corresponding increases in Vd and CL. Exposure to daptomycin in obese subjects (Cmax, AUC) was increased 25% and 30%, respectively, compared to nonobese matched controls, well within the range that was previously determined to be safe and well tolerated. Daptomycin may be dosed based on total body weight, and no adjustment in daptomycin dose or dose regimen should be required based solely on obesity.

Aging and Clinical Pharmacology: Implications for Antidepressants

Abstract: The elderly frequently have changes in pharmacokinetics, sensitivity to medications, homeostatic reserve (ability to tolerate physiological challenges), exposure to multiple medications, and adherence. All of these age-associated factors can potentially influence total exposure to medication, adverse effects, and subsequent treatment outcome. Most clinical trials are performed with healthy, younger adults. Extrapolating the results of these trials to the elderly may be inappropriate, particularly for the antidepressant treatment of depression. The authors review these age-associated differences and discuss their implications for antidepressant use in older adults.

Assessment of the Safety and Pharmacokinetics of Anidulafungin When Administered With Cyclosporine

Abstract: Anidulafungin is a novel antifungal agent of the echinocandin class that is intended for the treatment of invasive fungal disease. It is likely that anidulafungin will be coadministered with cyclosporine. In vitro studies and clinical studies were performed to evaluate the effect of anidulafungin on cyclosporine metabolism and to investigate the safety and pharmacokinetics of anidulafungin when concomitantly administered with cyclosporine. The potential for anidulafungin to inhibit the metabolism of cyclosporine was evaluated by pooled human hepatic microsomal protein fractions in vitro, incubating 3H-cyclosporine with different concentrations of anidulafungin. The safety of coadministration and the effects of cyclosporine on the pharmacokinetics of anidulafungin were assessed in a multiple-dose, open-label clinical study of 12 healthy volunteers. Subjects received a 200-mg intravenous loading dose of anidulafungin, followed by a daily 100-mg intravenous maintenance dose on days 2 through 8. An oral solution of cyclosporine (Neoral oral solution; 100 mg/mL) 1.25 mg/kg was also administered to subjects twice daily on days 5 through 8. In the in vitro study, the addition of anidulafungin had no effect on cyclosporine metabolism by human hepatic microsomal protein fractions. In the clinical study, no dose-limiting toxicities or serious adverse events occurred. A small increase in anidulafungin concentrations and drug exposure (22%) was observed after 4 days of dosing with cyclosporine and was not considered to be clinically relevant. The results support the concomitant use of anidulafungin and cyclosporine without the need for dosage adjustments of either drug.

Successful Projection of the Time Course of Drug Concentration in Plasma During a 1-Year Period From Electronically Compiled Dosing-Time Data Used as Input to Individually Parameterized Pharmacokinetic Models

Abstract: Pharmacokinetic studies rely on blood sampling at times relative to predefined dosing intervals. Intensive sampling is often done under direct observation of dose taking, which, though costly, virtually eliminates uncertainty about actual dosing times. In contrast, the sparse sampling done in population pharmacokinetic studies relies on patient-reported times of dosing, the accuracy of which the authors sought to assess by adding electronic monitoring to the usual patient reporting of dosing times. The study involved 35 antiretroviral-naive, human immunodeficency virus-infected patients and was designed to assess the safety, tolerability, pharmacokinetics, and antiviral activity of prescribed lopinavir/ritonavir (800/200 mg qd or 400/100 mg bid), stavudine, and lamivudine. The present research reports the pharmacokinetic analysis that results from taking into account the patients' actual dosing histories. Intensive sampling for plasma lopinavir concentrations was done at week 3, and 4 additional predose (trough) concentrations were measured during the next 12 months. Convergence was achieved by fitting a simple 1-compartment pharmacokinetic model, with first-order absorption and elimination, to the sparse sampling data, using electronic monitoring-reported times. In contrast, convergence was not achieved using the simple model when steady state was assumed, and the times for the last qd dose or the last 2 bid doses, as reported by the patient, were used as model input. Estimated individual pharmacokinetic parameters were then combined with electronic dosing histories to project each patient's internal drug exposure over long periods of time. This strategy may provide a basis for greatly increasing the informational yield and utility of conventional therapeutic drug monitoring.

Review of UCN-01 Development: A Lesson in the Importance of Clinical Pharmacology

Abstract: UCN-01 is a protein kinase inhibitor under development as a novel anticancer drug. The initial pharmacologic features in patients were not predicted from preclinical experiments. The distribution volume and the systemic clearance were much lower than those in experimental animals (mice, rats, and dogs), and the elimination half-life was unusually long (>200 hours). The unbound fraction in human plasma was also much smaller than that in dogs, rats and mice, as was the binding of UCN-01 to human alpha-1 acid glycoprotein much stronger than that to human serum albumin or human gamma-globulin. The association constants for alpha-1 acid glycoprotein and human plasma were approximately 8 x 10(8)(mol/L)(-1), indicating extremely high affinity. In this review article, the authors discuss the pharmacologic features of UCN-01 across species and provide a perspective on how this information could be applied prospectively to the future development of this agent.

Population pharmacokinetic analysis of dalbavancin, a novel lipoglycopeptide.

Abstract: Dalbavancin is a lipoglycopeptide antibiotic in clinical development as a once-weekly treatment for serious infections. A total of 532 patients, consisting of 502 patients with skin and soft tissue infections requiring parenteral therapy and 30 patients with catheter-related bloodstream infections, was available for population pharmacokinetic analysis. The majority of patients (78.4%) received dalbavancin intravenously as a 1000-mg dose on day 1 and a single 500-mg dose on day 8. A 2-compartment model with first-order elimination provided the best fit to the data. The clearance of dalbavancin was influenced by body surface area and creatinine clearance, but together they described less than 25% of the interpatient variability. Body surface area was determined to be a predictor of the central volume of distribution. There was no evidence that the presence of metabolic substrates, inhibitors, or inducers of cytochrome P450 or selected concomitant medications influenced the clearance of dalbavancin.

Comparison of the oropharyngeal deposition of inhaled ciclesonide and fluticasone propionate in patients with asthma.

Abstract: Ciclesonide is a novel inhaled corticosteroid that is converted in the lungs to its active metabolite, desisobutyryl-ciclesonide (des-CIC). The aim of this study was to compare the deposition of ciclesonide, as well as its conversion to des-CIC, in the oropharyngeal cavity with fluticasone propionate (FP) following inhalation via hydrofluoroalkane-propelled metered-dose inhalers (HFA-MDIs). Eighteen asthmatics inhaled ciclesonide 800 microg followed by FP 1000 microg or vice versa in an open, randomized, 2-treatment, 2-sequence study design. The oropharynx was washed out immediately and at 15, 30, 45, and 60 minutes after inhalation. Samples were analyzed for ciclesonide, des-CIC, and FP using liquid chromatography with tandem mass-spectrometric detection. Concentration-time curves and area under the concentration-time curve (AUC) were calculated for each drug. Ciclesonide and FP were recovered in almost all samples. Within 60 minutes after inhalation, the amounts of both ciclesonide and FP decreased sharply, and low residual levels were detected after 30 minutes. des-CIC was detected in relatively low concentrations, with maximum concentration 30 minutes following inhalation. The AUC(0-60 min) for ciclesonide (250.4 nmol x h/L) and des-CIC (37.8 nmol x h/L) were found to be significantly lower compared with FP (636.2 nmol.h/L, P < .001). Approximately 50% less ciclesonide and 90% less metabolite were present in the oropharynx compared with FP. Less than 20% of the residual ciclesonide in the oropharynx was metabolized to des-CIC. These findings indicate that oropharyngeal deposition of ciclesonide is only half that of FP following inhalation from an HFA-MDI. Furthermore, there is little activation of ciclesonide to its active metabolite in the oropharynx, suggesting a decreased likelihood of inhaled ciclesonide-associated oropharyngeal side effects.

Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects.

Abstract: The interactions of ranolazine, a new antianginal compound, with inhibitors and substrates of the CYP3A isoenzyme family were studied in 1 open-label and 4 double-blind, randomized, multiple-dose studies. In healthy adult volunteers, the authors sought (1) to determine the steady-state pharmacokinetics, safety, and tolerability of immediate- and sustained-release ranolazine with and without ketoconazole, diltiazem, or simvastatin and (2) to evaluate the effect of ranolazine on the pharmacokinetics of diltiazem, simvastatin, simvastatin metabolites, and HMG-CoA reductase activity. Ketoconazole increased ranolazine plasma concentrations and reduced the CYP3A4-mediated metabolic transformation of ranolazine, confirming that CYP3A4 is the primary metabolic pathway for ranolazine. Diltiazem reduced oral clearance of ranolazine in a dose-dependent manner. Simvastatin did not affect ranolazine pharmacokinetics, although ranolazine increased the AUC and C(max) of simvastatin, simvastatin acid, 2 simvastatin metabolites, and HMG-CoA reductase activity by <2-fold. Administration of ranolazine in combination with diltiazem or simvastatin was safe and well tolerated during the interval studied.

Concomitant tacrolimus and micafungin pharmacokinetics in healthy volunteers.

Abstract: Tacrolimus is an approved immunosuppressive agent and a known substrate for CYP3A. Micafungin is an echinocandin antifungal agent and a mild inhibitor of CYP3A metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of tacrolimus (5 mg oral) and micafungin (100 mg intravenous) alone and with concomitant administration (n=26). Tacrolimus area under the concentration-time curve was 298+/-135 microg*h/L when tacrolimus was administered alone, 305+/-129 microg*h/L (P=.8; confidence interval 89%, 118%) when tacrolimus was given with single-dose micafungin, and 282+/-138 microg*h/L (P=.4; confidence interval 82%, 107%) when tacrolimus was given with steady-state micafungin. Despite the mild inhibition of CYP3A in vitro by micafungin, there does not appear to be a drug interaction with tacrolimus and micafungin either with single-dose or steady-state micafungin administration.

Population pharmacokinetic analysis and simulation of the time-concentration profile of etanercept in pediatric patients with juvenile rheumatoid arthritis.

Abstract: This study was performed to estimate the population pharmacokinetic (PK) parameters of etanercept in pediatric juvenile rheumatoid arthritis (JRA) patients and to compare the steady-state time-concentration profiles between etanercept 0.8-mg/kg once-weekly and 0.4-mg/kg twice-weekly subcutaneous (SC) regimens by clinical trial simulation. To this end, mixed-effect analysis (NONMEM, Version 5.1) was performed using the etanercept PK database consisting of 69 JRA patients (4-17 years). Based on the population PK parameters obtained herein, a Monte Carlo clinical trial simulation experiment was conducted to compare the PK profiles in 200 virtual JRA patients who randomly received either etanercept 0.4 mg/kg SC twice weekly or 0.8 mg/kg once weekly for 12 weeks. The following population PK model could adequately describe etanercept PK profiles for twice-weekly SC dosing of 0.4 mg/kg: CL/F (L/h)=0.0576 (female) or 0.0772 (male) x (body surface area in m2/1.071)1.41, V/F(L)=7.88 x (body weight in kg/30.8). The means +/- standard deviations of simulated trough concentrations for 0.8-mg/kg once-weekly and 0.4-mg/kg twice-weekly dosing regimens were 1.58 +/- 1.07 mg/L and 1.92 +/- 1.09 mg/L, respectively. Peaks during 0.8-mg/kg once-weekly dosing (2.92 +/- 1.41 mg/L) were only 11% higher than during 0.4 mg/kg twice-weekly dosing (2.62 +/- 1.23 mg/L). In conclusion, the clinical trial simulation confirmed that 0.8-mg/kg once-weekly and 0.4-mg/kg twice-weekly SC regimens of etanercept are expected to yield overlapping steady-state time-concentration profiles, leading to equivalent clinical outcomes. This has been the basis of the recent Food and Drug Administration approval of the 0.8-mg/kg once-weekly regimen in pediatric patients with JRA.