Assessment of liquid captopril formulations used in children
TL;DR: Unlicensed captopril formulations are not bioequivalent to the licensed tablet form, or to each other, and so cannot be assumed to behave similarly in therapeutic use, and may require a period of increased monitoring of the patient.
Abstract: Objective Unlicensed liquid captopril formulations are commonly used to treat children with heart disease. This study assessed the bioequivalence of two liquid preparations against a licensed tablet form. Design An open label, single dose, three-treatment, three-period, crossover trial. Setting Outpatient. Patients Healthy adult volunteers (n=18). Interventions Each subject was randomly assigned to one of six dosing sequences, and dosed with 25 mg captopril on each of three dosing visits separated by a washout of at least 14 days. Blood samples for pharmacokinetic analysis were taken at regular intervals (0 min to 10 h) post-dose. Main outcome measures Bioequivalence of the formulations would be concluded if the 90% CI for the estimated ratio of the means of C max (maximum plasma concentrations) and area under curve(AUC) (extent of absorption) lay entirely within the range 0.8 to 1.25 Results Both liquid formulations failed the bioequivalence assessment with respect to C max and AUC. The 90% CI of the mean ratios of liquid/licensed tablet for both C max and AUC, fell outside the 0.8 to 1.25 limits. There was also considerable within-subject variability in C max (97.5%) and AUC (78.5%). Conclusions Unlicensed captopril formulations are not bioequivalent to the licensed tablet form, or to each other, and so cannot be assumed to behave similarly in therapeutic use. Thus formulation substitution must be done with care and may require a period of increased monitoring of the patient. There is also significant within-subject variability in performance which has clinical implications with respect to titrating to an optimum therapeutic dose.
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TL;DR: Compounding and manipulation of medicines in relation to approval by medicines regulators and non-approved preparation to fulfil the needs of the individual patient are explored.
51 citations
TL;DR: The results of this study support only a 7-day stability for the currently dispensed captopril OL in hospitals in Ireland, while the FDTs may represent an alternative and convenient oral solid extemporaneous preparation ofCaptopril and, potentially, other extemportaneous pediatric medications.
20 citations
TL;DR: Palatability is often assessed in clinical trials of pediatric dosage forms through the utilization of 2 unvalidated, yet widely accepted, visual scales and there is no standard statistical methodology for analyzing the results of these scales or the cross-comparison of results across studies.
Abstract: Background: Palatability and swallowability of oral dosage forms are important considerations in the development of medications for pediatric populations. As a result of recent legislation, the number of pharmaceutical products being developed with formulations for children is increasing. However, there are limited recommendations and published literature regarding appropriate palatability and swallowability assessment scales in pediatric patients. Objective: This systematic literature review aimed to identify and evaluate tools currently utilized to assess palatability and swallowability in clinical trials for pediatric oral dosage forms and identify any potential relationships between palatability and treatment adherence. Literature databases were searched for clinical trials that evaluated palatability of oral dosage forms targeted for pediatric patients. The searches were limited to papers in the English language from January 2008 to March 2013. Results: A total of 137 citations were identified, with 27 articles included in the final full-text analysis. Conclusions: Various limitations to this systematic review exist, primarily focused on the unavailability of published, early phase development data related to palatability. However, based on results of this review, palatability is often assessed in clinical trials of pediatric dosage forms through the utilization of 2 unvalidated, yet widely accepted, visual scales. There is no standard statistical methodology for analyzing the results of these scales or the cross-comparison of results across studies. Limited evidence regarding a correlation between palatability and treatment adherence in pediatric patients was identified.
16 citations
Dissertation•
12 Jan 2014
TL;DR: The results indicate that both solid and liquid oral dosage forms may provide suitable solutions to treat paediatric patients of different ages and that the individual needs of each child’s in nifedipine medication can be satisfied with these age-appropriate dosage forms.
Abstract: Despite efforts to improve the availability of commercial drug products for children, there is still a widespread need for compounded preparations. Age-appropriate dosage forms formulated at different strengths containing harmless excipients are routinely needed. Therefore, hospital pharmacies still compound a wide range of preparations although there are no appropriate and comprehensive published standards. The present study examined the chemical and physical stabilities and content uniformities of one compounded, nifedipine in 1 mg oral dosage forms by using reproducible and validated stabilityindicating high performance liquid chromatography (HPLC) methods. Individually weighed oral powders, hard gelatin capsules and unit-dose or multi-dose suspensions were compounded either by using a crushed commercial tablet or from nifedipine drug powder. The results indicate that both solid and liquid oral dosage forms may provide suitable solutions to treat paediatric patients of different ages. The total mass of the nifedipine oral powder had to be 300 mg or more in order to ensure accurate dosage. When the mass was 100 mg or 50 mg, the nifedipine amount was less than 80% of the targeted amount. Most of the missing amount was located on the emptied powder papers. Nifedipine capsules, sizes 1–4 (0.21–0.50 ml), whose contents were emptied prior to use, do represent a good alternative to oral powders when comparing the recovery. Nifedipine 1 mg/ml unit-dose suspension in hypromellose 1% was chosen as the formulation for administration via nasogastric feeding tubes. Oral powders were chemically stable for the studied period of 12 months and unit-dose suspensions were chemically, physically and microbiologically stable for four weeks, at room temperature or in the refrigerator. Due to the light sensitivity of nifedipine, it required protection from light during handling and storage. When exposed to artificial daylight, 20–30% photodegradation occurred within three hours. The content uniformities of the nifedipine unit-dose suspensions, powders and capsules met the requirements of the European Pharmacopoeia. Vigorous agitation, i.e. inverting the bottle 10-15 times instead of three times, was critical for ensuring the content uniformity of nifedipine 1 mg/ml multi-dose suspensions compounded with extemporaneous vehicles. In contrast, nifedipine 1 mg/ml multidose suspensions passed the test if the bottle was inverted only three times when more sophisticated commercial suspension vehicles were used. In conclusion, compounded nifedipine oral powders and unit-dose suspensions were stable and uniform throughout the study periods when protected from light. Emptying of capsules represents an alternative to oral powders. The agitation of suspension vehicle is important to ensure the quality of oral multi-dose suspensions. The individual needs of each child’s in nifedipine medication can be satisfied with these age-appropriate dosage forms. National Library of Medicine Classification: QV 754, QV 779, QV 786, WX 179 Medical Subject Headings: Pharmacy Service, Hospital; Pediatrics; Pharmaceutical Preparations; Drug Compounding; Dosage Forms; Capsules; Powders; Suspensions; Nifedipine; Drug Stability; Chromatography, High Pressure Liquid
8 citations
TL;DR: The article by Mulla et al in this month's Drug therapy is a good example of how one specific aim of the Paediatric Regulation can be put into practice and clinical trials in children avoided.
Abstract: Clinical trials of medicines in children are essential. So it may seem strange, despite recent lobbying and legislation, to discuss when clinical trials in children can be avoided. One specific aim of the Paediatric Regulation was that it should improve the health of children in Europe without subjecting children to unnecessary trials.1 A clinical trial in children should only take place when the information cannot be gained from a trial in the adult population. This should always be kept in mind when planning a protocol. Can the information be reliably obtained from adults? The article by Mulla et al in this month's Drug therapy is a good example of how this can be put into practice and clinical trials in children avoided.2
Differences in pharmacokinetics and pharmacodynamics, and adverse reactions, are common in children compared to adults. Growth and maturation processes, as well as certain specific diseases, are unique to children.3 However, it is rare that a phase I study takes place in children. Phase I trials are the first stage of testing in …
6 citations
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TL;DR: It is suggested that a Biopharmaceutics Drug Disposition Classification System (BDDCS) using elimination criteria may expand the number of Class 1 drugs eligible for a waiver of in vivo bioequivalence studies and provide predictability of drug disposition profiles for Classes 2, 3, and 4 compounds.
Abstract: The Biopharmaceutics Classification System (BCS) was developed to allow prediction of in vivo pharmacokinetic performance of drug products from measurements of permeability (determined as the extent of oral absorption) and solubility. Here, we suggest that a modified version of such a classification system may be useful in predicting overall drug disposition, including routes of drug elimination and the effects of efflux and absorptive transporters on oral drug absorption; when transporter-enzyme interplay will yield clinically significant effects (e.g., low bioavailability and drug-drug interactions); the direction, mechanism, and importance of food effects; and transporter effects on postabsorption systemic drug concentrations following oral and intravenous dosing. These predictions are supported by a series of studies from our laboratory during the past few years investigating the effect of transporter inhibition and induction on drug metabolism. We conclude by suggesting that a Biopharmaceutics Drug Disposition Classification System (BDDCS) using elimination criteria may expand the number of Class 1 drugs eligible for a waiver of in vivo bioequivalence studies and provide predictability of drug disposition profiles for Classes 2, 3, and 4 compounds.
1,292 citations
TL;DR: It is suggested that lisinopril is a poor substrate for the di/tripeptide carrier in Caco‐2 cells, consistent with the greater oral availability and time‐dependent absorption profile of enalapril maleate and captopril, compared to lisinobril.
Abstract: 1. The role of proton-linked solute transport in the absorption of the angiotensin-converting enzyme (ACE) inhibitors captopril, enalapril maleate and lisinopril has been investigated in human intestinal epithelial (Caco-2) cell monolayers. 2. In Caco-2 cell monolayers the transepithelial apical-to-basal transport and intracellular accumulation (across the apical membrane) of the hydrolysis-resistant dipeptide, glycylsarcosine (Gly-Sar), were stimulated by acidification (pH 6.0) of the apical environment. In contrast, transport and intracellular accumulation of the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, were low (lower than the paracellular marker mannitol) and were not stimulated by apical acidification. Furthermore, [14C]-lisinopril transport showed little reduction when excess unlabelled lisinopril (20 mM) was added. 3. pH-dependent [14C]-Gly-Sar transport was inhibited by the orally-active ACE inhibitors, enalapril maleate and captopril (both at 20 mM). Lisinopril (20 mM) had a relatively small inhibitory effect on [14C]-Gly-Sar transport. pH-dependent [3H]-proline transport was not inhibited by captopril, enalapril maleate or lisinopril. 4. Experiments with BCECF[2',7',-bis(2-carboxyethyl)-5(6)-carboxyfluorescein]-loaded Caco-2 cells demonstrate that dipeptide transport across the apical membrane is associated with proton flow into the cell. The dipeptide, carnosine (beta-alanyl-L-histidine) and the ACE inhibitors enalapril maleate and captopril, all lowered intracellular pH when perfused at the apical surface of Caco-2 cell monolayers. However, lisinopril was without effect. 5. The effects of enalapril maleate and captopril on [14C]-Gly-Sar transport and pHi suggest that these two ACE inhibitors share the H(+)-coupled mechanism involved in dipeptide transport. The absence of pH-dependent [14C]-lisinopril transport, the relatively small inhibitory effect on [14C]-Gly-Sar transport,and the absence of lisinopril-induced pHi changes, all suggest that lisinopril is a poor substrate for thedi/tripeptide carrier in Caco-2 cells. These observations are consistent with the greater oral availability and time-dependent absorption profile of enalapril maleate and captopril, compared to lisinopril.
77 citations
TL;DR: A specific high performance liquid chromatography-mass spectrometric (LC-MS/MS) assay was developed for the determination ofcaptopryl in plasma and was applied to study bioequivalence of captopril in a group of 25 human subjects at a single oral dose of a 50mg tablet.
32 citations
"Assessment of liquid captopril form..." refers background in this paper
...The 90% CIs for both unlicensed liquid formulations (A & B) fell outside accepted criteria (80% to 125%) for bioequivalence (7)....
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TL;DR: The various causes of ventricular dysfunction and congestive heart failure in infants, children, and adolescents are reviewed; the data available regarding treatment of these conditions with ACE inhibitors, and the safety and efficacy of these drugs for the various conditions are reviewed.
27 citations
TL;DR: In heart failure due to left-to-right shunts a similar activation of compensatory neurohormonal mechanisms as in adults with chronic heart failure was found and treatment of these activated compensatory mechanisms with angiotensin-converting enzyme inhibitors and beta-blockers showed beneficial effects in pediatric patients.
Abstract: Paradigms in understanding heart failure have changed as the knowledge of pathophysiology and its molecular basis has deepened. In the chronic compensated state of heart failure recent research has focussed on the body's regulatory mechanisms. Today heart failure is understood as a complex interplay of hemodynamic and neurohormonal factors. In pediatrics a large variety of heterogeneous conditions cause heart failure. Some require special therapeutic approaches such as the infusion of prostaglandin for ductal patency, the careful maintenance of balance between systemic and pulmonary circulations or operative treatment. In newborns with critical congenital lesions and in patients in the postoperative period management of acute heart failure becomes important. Chronic heart failure as it is understood today is present in patients with cardiomyopathies and in an increasing number of pediatric patients after palliative surgery. In heart failure due to left-to-right shunts a similar activation of compensatory neurohormonal mechanisms as in adults with chronic heart failure was found. In small clinical trials treatment of these activated compensatory mechanisms with angiotensin-converting enzyme inhibitors and beta-blockers showed beneficial effects in pediatric patients. However large clinical multicenter trials as performed in the adult population should be conducted.
27 citations