An Alternative Approach for Assessment of Rate of Absorption in Bioequivalence Studies

The partial area method was investigated for evaluation of equivalency in the rate of absorption of immediate release formulations. The applicability of the method was demonstrated with four drugs with different pharmacokinetic/pharmacodynamic characteristics. The confidence interval approach currently employed for bioequivalence determinations was applied to the relevant absorption parameters, including C _max and partial AUCs. The method was found to be more discriminating than C _max and/or T _max in the evaluation of the absorption rate of drugs. The cutoff time or point for partial AUC calculation may vary with the type of drug under study, depending on its clinical use and onset of action. The method was shown to be useful in the assessment of rate of absorption in bioequivalence studies.     

Why Rate of Absorption Inferences in Single Dose Bioequivalence Studies are Often Inappropriate

Purpose. Peak drug concentration (C_max) measures the extremity of drug exposure and is a secondary indicator of the extent of absorption after area under the concentration time curve (AUC). C_max serves as the indicator of absorption rate in bioequivalence (BE) studies in the US (1). The use of C_max, not the time to Cmax(Tmax), as the metric to assess absorption rate causes erratic inferences in BE studies, and incorrect conclusions for some. We can improve BE efficiency (i.e., get the answer right the first time), by properly analyzing the time to C_max(T_max) instead of C_max. Methods. We have previously redirected attention to T_max as the unconfounded absorption rate variable, instead of Cmax, and have called for equally spaced sampling times during the suspected absorption phase to improve the performance of the rate metric (2). Equal spacing converts T_max easily into a count variable and we illustrated an appropriate statistical analysis for counts. This paper provides some measurement theory concepts to help judge which is the more appropriate analysis, and also provides parametric confidence limits for T_max treatment differences. Three separate BE studies are then analyzed by both methods. Results. By focusing on the differences in conclusions, or inferences, this paper identifies three major issues with the current FDA "recommended analysis of BE studies. First, C_max, a continuous variable peak-height or extent measure has usurped T_max's function and performs erratically as a substitute measure for the rate of absorption. Second, T_max, should be analyzed as a discrete attribute, not as a continuous variable. Third, since several extent measures (AUC, C_max), not one, are actually being analyzed, an adjustment for multiple testing is mandatory if we are to maintain the size of the test at the desired level (13), and not inadvertently use a narrower bioequivalence window than is intended. These actions all can have serious unintended consequences on inferences, including making inappropriate ones.     

Rationale and conditions for the requirement of chiral bioanalytical methods in bioequivalence studies

Purpose

The aim of the present work was to assess the need for chiral bioanalytical methods in bioequivalence studies.

Methods

The samples from a bioequivalence study of two ibuprofen 2% oral suspensions that had shown bioequivalence for AUC and C_max, but not for t_max (medians of 2.0 and 0.75 h) with a non-chiral method were assayed with a chiral method to investigate whether there was an actual difference in the rate of absorption within the limits of C_max and AUC bioequivalence.

Results

The non-chiral method and the sum of concentrations of both enantiomers obtained with the chiral method gave a similar outcome (90% CI C_max non-chiral: 82.77–96.09, sum of enantiomers: 82.19–98.23; 90% CI AUC_t non-chiral: 107.23–115.49, sum of enantiomers: 105.73–121.35). However, the chiral method showed differences in AUC and C_max that resulted in non-bioequivalence for the individual enantiomers (90% CI C_max S-ibuprofen: 76.05–91.36, R-ibuprofen: 87.84–113.05; 90% CI AUC_t S-ibuprofen: 96.67–105.86, R-ibuprofen: 118.86–142.24). The differences in the pharmacokinetics of each enantiomer, and thus in the enantiomer concentration ratio, were dependent on the rate of absorption.

Conclusions

Due to the fact that in bioequivalence studies the rate of absorption of the new product is unknown, chiral bioanalytical methods should be employed for chiral drugs, such as ibuprofen, whose enantiomers exhibit different pharmacodynamic characteristics and whose enantiomer concentration ratio might be modified by the rate of absorption, irrespective of whether the eutomer is the minor enantiomer or the similarity of the pharmacokinetics of the enantiomers at a given rate of absorption.     

Pharmacokinetics of Ibuprofen Enantiomers in Humans Following Oral Administration of Tablets with Different Absorption Rates

Ibuprofen (IB) is a racemic drug and is administered as such. While activity is due mainly to the S enantiomer, pharmacokinetic interpretations, as well as criteria to assess the bioequivalence of IB formulations, are based on measurements of the total (S + R) drug concentrations. IB enantiomers possess different disposition properties mainly as a result of R-to-S isomeric bioinversion. Inversion is maximal during the absorption phase, suggesting, perhaps, involvement of a presystemic process. This concept was evaluated in healthy subjects by crossover administration of four IB tablets having different absorption rates. The plasma concentrations of the individual isomers were measured using a stereospecific gas chromatographic assay. Differences among the products were insignificant with respect to the extent to the absorption. The S:R concentration ratios rose for 4 to 6 hr and then remained relatively unchanged. This observation was consistent with equal terminal t _1/2 values for the enantiomers. There were significant differences between the peak times (T _max) of the products. The S:R ratios of the concentrations at T _max of S and AUC also differed; significant positive correlations were found between T _max and the S:R ratios of C _max. Thus the extent of R-to-S inversion, and hence the potency of a racemic dose of IB, may be absorption rate dependent.     

Using Partial Area for Evaluation of Bioavailability and Bioequivalence

Assessment of bioavailability/bioequivalence generally relies on the comparison of rate and extent of drug absorption between products. Rate of absorption is commonly expressed by peak concentration (C_max) and time to peak concentration (T_max), although these parameters are indirect measures of absorption rate. Recognizing the importance of systemic exposure to drug efficacy and safety, FDA recommended that systemic exposure be better used for bioavailability/bioequivalence assessment. Apart from peak exposure and total exposure, FDA also recommended a new metric for early exposure that is considered necessary when a control of input rate is critical to ascertain drug efficacy and/or safety profile. The early exposure can be measured by truncating the area under the curve at T_max of the reference product (PAUC_r,tmax) or some designated early time after dosing. The choice of truncation is most appropriately based on PK/PD relationship or efficacy/safety data for the drug under examination. Compared with C_max, PAUC_r,tmax has higher sensitivity in detecting formulation differences and may be more variable. If the metric is highly variable, the reference-scaling approach can be employed for bioequivalence evaluation. The partial area metric is useful in PK/PD characterization as well as in the evaluation of bioavailability, bioequivalence and/or comparability.     

A Review of: “Statistics: Concepts and Controversies,Sixth Edition,by D. S. Moore and W. I. Notz (Eds.)”

Contrasts were evaluated for the maximum blood or plasma concentration (C _max) of drugs measured after repeated and single oral administrations. Variances C _max of were calculated and also simulated for a single drug as well as the comparison of two formulations, i.e., for the analysis of investigations of both bioavailability and bioequivalence. The coefficient of variation (C V) of C _max was higher in the steady state than after a single drug administration when the variability of the disposition rate constant (k) was substantially larger than that of the absorption rate constant (k_a )In turn, the CV of C _max was substantially lower following repeated than after single drug administration when the variability of k_a dominated that of k.The latter condition often prevails in practice since the relative variation of absorption rates generally substantially exceeds that of clearance (the latter being proportional to k) The statistical insensitivity is superimposed on the low kinetic sensitivity exhibited by C _maxfollowing repeated drug administrations. Consequently, bioequivalence trials conducted in the steady state generally permit a declaration of equivalence even between drug products that have very different absorption rates     

Bioequivalence study of nabumetone tablets in man

A nabumetone tablet in development (Nabuton^R) was tested for its bioequivalence to the reference tablet (Uniton^R). Seventeen healthy Korean male subjects participated in this study. Each subject received a 1-g dose of nabumetone (2 tablets each) in an unbalanced, randomized, two-way crossover investigation. Serum concentrations of 6-methoxy-2-naphthylacetic acid (6-MNA), a major metabolite of nabumetone, were measured over 120 hr interval by a high-performance liquid chromatography. The maximum serum concentration (C_max) and time to reach the maximum concentration (T_max) were read directly, but area under the serum concentration time curve from time 0 to 120 hr (AUC) and mean residence time (MRT) of 6-MNA were calculated from the serum 6-MNA concentration-time curves. The serum curves showed multiple peaks of 6-MNA in most subjects, and the C_max and T_max were read from the highest serum peaks. Calculated bioavailability parameters for test and reference tablets were 1498.6∶1377.9 μg·hr/ml for AUC; 25.2∶23.1 μg/ml for C_max; 11.8∶16.4 hr for T_max and 42.6∶43.8 hr for MRT, respectively. The pairedt-test revealed no significant differences in all the parameters between the two tablets. Analysis of variance (ANOVA) revealed no significant differences between groups and formulations in all the parameters (C_max, T_max, AUC and MRT) indicating the crossover design of the experiment was properly performed. But significant differences (p<0.05) between subject/groups and periods were found for all the parameters indicating substantial intersubject and interperiodic variations for these parameters.     

Intra- and Inter-Subject Variabilities of CGP 33101 after Replicate Single Oral Doses of Two 200-mg Tablets and 400-mg Suspension

Purpose. The purpose of this study was to use a replicate designed trial to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters of CGP 33101 after oral administration of tablets relative to that of powder suspended in water, and to determine the relative proportion of the intra-subject variance to the overall variability. Methods. Sixteen healthy subjects were randomly assigned to four groups to receive tablets and suspension twice in four different treatment sequences. The plasma concentration-time profile of CGP 33101 was characterized in terms of C_max, T_max, and AUC. Bioavailability of tablets relative to suspension and intra- and inter-subject variability were assessed by statistical analysis. Results and Conclusions. The overall variabilities in absorption kinetics of CGP 33101 in healthy subjects were small with CV's of the population mean values for AUC and C_max less than 26% for both tablets and suspension. Contribution of intra-subject variability to the overall variability was also small (~20%). Both the overall and intra-subject variabilities of AUC and C_max after suspension were larger than after the tablets. However, the differences in variability between tablets and suspension were not statistically significant (p > 0.05). The tablet formulation was bioequivalent to suspension in terms of rate and extent of absorption based on 90% conventional confidence intervals (for AUC and C_max) and Wilcoxon rank-sum test (for T_max).     

Absorption Rate Vs. Exposure: Which Is More Useful for Bioequivalence Testing?

Purpose. The goals were to evaluate the usefulness of C_max/AUC_lqc, ratio of the maximum plasma drug concentration to the area under the plasma concentration-time curve to the time of the last quantifiable concentration, in bioequivalence testing and to explore the use of exposure as a replacement for the concepts of rate and extent of drug absorption. Methods. The bioequivalence of products differing in both rate (ka) and extent (F) of absorption was assessed under conditions similar to those encountered in a typical trial. A one-compartment model drug with first-order absorption (rate constant = ka) and elimination was used. Variability was introduced in all model parameters using Monte Carlo techniques. The results were expressed in terms of the probability of declaring bioequivalence in a cross-over trial with 24 subjects using C_max/AUC_lqc, AUC_lqc, and C_max as bioequivalence measures. Results. The outcome of a bioequivalence trial was shown to depend on the measure. C_max/AUC_lqc reflected changes in ka, but not in F. AUC_lqc showed dependence on F, but virtually no dependence on ka. For C_max, a 3- to 4-fold increase in ka and a concomittant 20% decrease in F, as well as corresponding changes in the opposite directions, resulted in bioequivalent outcomes. Conclusions. It was concluded that use of C_max/AUC_lqc should be discouraged and that defining bioequivalence in terms of rate and extent of absorption has major problems. The goal of bioequivalence trials should be to assure that the shape of the concentration-time curve of the test product is sufficiently similar to that of the reference product. To this end, the use of exposure rather than rate and extent of absorption concepts is encouraged.     

Prediction of Pharmacokinetic Parameters and the Assessment of Their Variability in Bioequivalence Studies by Artificial Neural Networks

Purpose. The methodology of predicting the pharmacokinetic parameters (AUC, c_max, t_max) and the assessment of their variability in bioequivalence studies has been developed with the use of artificial neural networks. Methods. The data sets included results of 3 distinct bioequivalence studies of oral verapamil products, involving a total of 98 subjects and 312 drug applications. The modeling process involved building feedforward/backpropagation neural networks. Models for pharmacokinetic parameter prediction were also used for the assessment of their variability and for detecting the most influential variables for selected pharmacokinetic parameters. Variables of input neurons based on logistic parameters of the bioequivalence study, clinical-biochemical parameters, and the physical examination of individuals. Results. The average absolute prediction errors of the neural networks for AUC, c_max, and t_max prediction were: 30.54%, 39.56% and 30.74%, respectively. A sensitivity analysis demonstrated that for verapamil the three most influential variables assigned to input neurons were: total protein concentration, aspartate aminotransferase (AST) levels, and heart-rate for AUC, AST levels, total proteins and alanine aminotransferase (ALT) levels, for c_max, and the presence of food, blood pressure, and body-frame for t_max. Conclusions. The developed methodology could supply inclusion or exclusion criteria for subjects to be included in bioequivalence studies.     

Improved Human Pharmacokinetic Prediction of Hepatically Metabolized Drugs With Species-Specific Systemic Clearance

Accurate prediction of human pharmacokinetics (PK) is important for the choice of promising compounds in humans. As the predictability of human PK by an empirical approach is low for drugs with species-specific PK, the utility of a physiologically based pharmacokinetic (PBPK) model was verified using 16 hepatically metabolized reference drugs. After the prediction method for total clearance (CL_tot) and distribution volume at steady state (Vd_ss) in the conventional PBPK model had been optimized, plasma concentrations following a single oral administration of each reference drug to healthy volunteers were simulated, and the prediction accuracy for human PK was compared between empirical approaches and the optimized PBPK model. In the drugs with low species-specific CL_tot, there was little difference in predictability for maximum concentration (C_max), time to maximum plasma concentration (T_max), and area under the curve (AUC) (absolute average fold error: 1.3-2.4). In contrast, the optimized PBPK model predicted C_max and AUC of the drugs with high species-specific CL_tot with lower absolute average fold error (C_max and AUC: 2.8 and 3.2, respectively) than those of the empirical approach (C_max and AUC: 2.6-4.9 and 3.9-10.7, respectively). Therefore, the optimized PBPK model is useful for human PK prediction of drugs with species-specific CL_tot.     

疾病以及配伍对人参皂苷在大鼠体内的药动学影响

目的 建立SD大鼠血浆中人参皂苷Rb1、Rb2和Rg1的HPLC分析方法,对比分析配伍白术挥发油前后,人参皂苷在慢性萎缩性胃炎模型大鼠体内药动学特征。方法 SD大鼠分为4组,其中单用正常组和单用模型组均给药人参总皂苷292 mg·kg^-1,配伍正常组和配伍模型组均给药人参总皂苷292 mg·kg^-1和白术挥发油0.1 mL·kg^-1。于给药前和给药后不同时间点进行眼眶取血,采用HPLC测定各成分的血药浓度,并采用Winnolin 6.3软件计算其药动学参数。结果 与单用正常大鼠比较,单用模型组大鼠体内人参皂苷Rb1的C_max和AUC值降低,T_max、T_1/2以及MRT增加,人参皂苷Rb2和Rg1则呈现出AUC增加的变化;而配伍正常组大鼠体内人参皂苷Rb1、Rb2和Rg1的C_max和AUC值均增加,T_max、T_1/2以及MRT值均缩短。与单用模型组大鼠比较,配伍模型组大鼠体内人参皂苷Rb1和Rg1的C_max和AUC值均增加,T_max、T_1/2以及MRT值均降低。结论 在相同给药剂量下,疾病状态机体对人参皂苷的吸收和代谢呈现缓慢趋势,而配伍后能促进皂苷成分在体内的吸收,同时加快代谢消除,为人参的临床用药提供参考依据。     

Effect of Dose and Ointment Application Technique on Nitroglycerin Plasma Concentrations

Each of ten non-smoking, healthy male volunteers between the ages of 20 and 30 and within 10% of their ideal body weight received four nitroglycerin ointment (NTG-O) treatments: ½″ NTG-O over 3.94 in² and 7.88 in², and 1″ NTG-O over 3.94 in² and 7.88 in² in a randomized order. Eleven blood samples and 22 determinations of heart rate and blood pressure were obtained over each 6-hour study period. Nitroglycerin plasma concentrations were determined by gas-liquid chromatography with electron capture detection. Area under the nitroglycerin plasma concentration-time curve (AUC), peak plasma concentration (C_max), and time to peak concentration (T_max) were determined for each study. C_max and AUC values were corrected for the actual dose applied. Differences between AUC, C_max and T_max were tested using repeated measures analysis of variance. Change in surface area had no statistically significant effect on AUC, C_max and T_max. Mean AUC for the ½″ and 1″ doses differed (648 vs 2003 ng.ml⁻¹ min, p = 0.016), as did C_max (4.6 vs 12.4 ng.ml⁻¹, p = 0.022); however, there was no correlation between individual doses and AUCs. Generally, NTG plasma concentrations within the proposed therapeutic range of 1.2–11.1 ng.ml⁻¹ were detectable throughout each study interval. These data suggest that continuous absorption occurred throughout the 6-hour dosing interval, that a trend toward increased AUC and C_max occurred with the larger surface area, and that, in general, doubling the dose of NTG-O doubles the AUC.     

The effect of HPMC—a cholesterol-lowering agent—on oral drug absorption in dogs

The objective of this study was to evaluate the effects which hydroxypropylmethylcellulose (HPMC) may exert on oral drug absorption, in cases where this soluble fiber is administered to regulate blood lipid levels. Studies were conducted in vitro and in healthy female mongrel dogs using two different grades of HPMC, i.e. K8515 HPMC and ultra high molecular weight (UHMW) HPMC. The maximum plasma concentration, C_max, of paracetamol and both the C_max and the area under the concentration–time curve, AUC, of cimetidine were significantly decreased by the coadministration of 10 g of K8515 HPMC or 7.5 g of UHMW HPMC dissolved in 500 mL normal saline under fasting conditions. No statistically significant effects were observed on hydrochlorothiazide or mefenamic acid absorption. Based on in vitro data and previous studies it appears that reductions in gastric emptying and dissolution rate of paracetamol account for the effect observed in vivo. For cimetidine, a drug which can be absorbed from both the small and the large intestine, the indigestibility of HPMC in the colon in addition to the great reduction of dissolution rate led to reductions of both the C_max and AUC values. The long T_max values, even in the absence of HPMCs and the more modest reduction of the dissolution rate of hydrochlorothiazide by the HPMCs are thought to have precluded the observation of any significant alterations in the in vivo absorption profile. Owing to its erratic absorption, no statistically based conclusion could be drawn about the effects of coadministered HPMC on the oral absorption of the poorly soluble mefenamic acid. It is concluded that the effects of HPMCs on drug absorption in dogs are most pronounced for compounds with absorption profiles that are dependent on gastric emptying, i.e. compounds that are highly water soluble and that exhibit short T_max values. Compounds with long absorption profiles appear to be less susceptible to changes in absorption behavior due to coadministration of HPMCs. Copyright © 1998 John Wiley & Sons, Ltd.     

Bioequivalence evaluation of sparse sampling pharmacokinetics data using bootstrap resampling method

ABSTRACT

Bioequivalence studies are an essential part of the evaluation of generic drugs. The most common in vivo bioequivalence study design is the two-period two-treatment crossover design. The observed drug concentration–time profile for each subject from each treatment under each sequence can be obtained. AUC (the area under the concentration–time curve) and C_max (the maximum concentration) are obtained from the observed drug concentration–time profiles for each subject from each treatment under each sequence. However, such a drug concentration–time profile for each subject from each treatment under each sequence cannot possibly be available during the development of generic ophthalmic products since there is only one-time point measured drug concentration of aqueous humor for each eye. Instead, many subjects will be assigned to each of several prespecified sampling times. Then, the mean concentration at each sampling time can be obtained by the simple average of these subjects’ observed concentration. One profile of the mean concentration vs. time can be obtained for one product (either the test or the reference product). One AUC value for one product can be calculated from the mean concentration–time profile using trapezoidal rules. This article develops a novel nonparametric method for obtaining the 90% confidence interval for the ratio of AUC_T and AUC_R (or C_T,max/C_R,max) in crossover studies by bootstrapping subjects at each time point with replacement or bootstrapping subjects at all sampling time points with replacement. Here T represents the test product, and R represents the reference product. It also develops a novel nonparametric method for estimating the standard errors (SEs) of AUC_h and C_h,max in parallel studies by bootstrapping subjects treated by the hth product at each time point with replacement or bootstrapping subjects treated by the hth product at all sampling time points with replacement, h = T, R. Then, 90% confidence intervals for AUC_T/AUC_R and C_T,max/C_R,max are obtained from the nonparametric bootstrap resampling samples and are used for the evaluation of bioequivalence study for one-time sparse sampling data.     

Bioequivalence: Performance of Several Measures of Extent of Absorption

The determination of the area under the concentration–time curve (AUC) is the method most commonly used by regulatory agencies to assess extent of drug absorption after single-dose administration of oral products. Using simulations, several approaches toward measuring the actual area, in whole or part, were tested. In addition, the performance of the peak concentration (C _max), usually taken as a measure of the rate of absorption was assessed evaluating extent. Model scenarios for drugs with typical mean characteristics and statistical distributions were investigated. Using different kinetic models of disposition, the time course of the drug concentration in plasma was simulated. Intraindividual and interindividual variability and assay error were modeled using Monte Carlo techniques. The accuracy, precision, and ease of use of the various measures of extent were evaluated, and statistical power analyses were performed. Among the measures tested, the most reliable were the AUC computed up to the time of the last quantifiable concentration, without extrapolation, and C _max. However, being also sensitive to rate, C _max as a measure of extent is of limited potential.     

Bioequivalence of a Highly Variable Drug: An Experience with Nadolol

Purpose. To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard^® 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUC_t, AUC, and C_max in bioequivalence determinations. Methods. Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of C_max. Results. Fasted and food-effect studies of the 160mg tablet clearly established bioequivalence and revealed an unexpected reduction in nadolol bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUC_t and AUC. However, C_max criteria proved extremely difficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable number of subjects. Conclusions. Final results clearly established bioequivalence of both strengths and characterized an unexpected food effect which did not appear to be formulation-related. However, the C_max of nadolol is only slightly sensitive to absorption rate and the relatively large variability of C_max reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.     

Pharmacokinetics and Bioequivalence of Two Amoxicillin 500 mg Products: Effect of Food on Absorption and Supporting Scientific Justification for Biowaiver

PurposeAims of this study were to compare the bioequivalence of two formulations of amoxicillin 500 mg capsules under fasted and fed conditions in the same set of healthy volunteers, compare pharmacokinetics of amoxicillin under the two conditions and to assess the possibility of predicting in vivo bioequivalence of the two formulations using in vitro dissolution data.MethodThe innovator product of amoxicillin was used as the reference formulation and a test product, which showed in vitro equivalence after a biowaiver study with the same reference product was used in the bioequivalence study. Altogether 16 subjects were randomized to the reference and test products in the fasted study and 12 of them participated in the fed study. Plasma concentration of amoxicillin was analyzed by a validated Liquid chromatography coupled with two mass spectrometry (LC-MS/MS) method. Noncompartmental analysis was used to determine the pharmacokinetic parameters. Average bioequivalence method was used to evaluate the bioequivalence of the two formulations and statistical significance of the pharmacokinetic parameters were tested to study the effect of food on amoxicillin absorption.ResultsThe Geometric Mean Ratio (GMR) for the test/reference product for the maximum drug concentrations (C_max) was 102.77% and 97.38% in fasted and fed conditions respectively which was within 80.00–125.00% range required to demonstrate bioequivalence. The GMR for test/reference products for the area under the curve (AUC_0-8,) was 100.05% and 96.91% in fasted and fed conditions respectively meeting the bioequivalence criteria. For the reference product, the C_max was 9.38 and 7.61 µg x mL⁻¹(p =0.0224), time to reach maximum concentration (T_max) was 1.73 and 3.02 h (p=0.0005) and AUC_0-8 was 26.02 and 25.54 µg/h⁻¹ mL⁻¹ p = 0.672) under fasted and fed conditions respectively.ConclusionThe test and the reference formulations were bioequivalent under both fasted and fed conditions. Although the C_max was significantly lower and T_max was significantly delayed under fed conditions, it did not affect the AUC. Therefore, being a time dependent antibiotic, clinically significant effect of food on efficacy of amoxicillin is unlikely. As the selected products were equivalent in vitro, these findings support scientific justification for conducting in vitro dissolution studies for solid oral amoxicillin products as a surrogate for in vivo bioequivalence studies.     

Effects of concurrent administration of nevirapine on the disposition of quinine in healthy volunteers

Objectives Nevirapine and quinine are likely to be administered concurrently in the treatment of patients with HIV and malaria. Both drugs are metabolised to a significant extent by cytochrome P450 (CYP)3A4 and nevirapine is also an inducer of this enzyme. This study therefore evaluated the effect of nevirapine on the pharmacokinetics of quinine. Methods Quinine (600 mg single dose) was administered either alone or with the 17th dose of nevirapine (200 mg every 12 h for 12 days) to 14 healthy volunteers in a crossover fashion. Blood samples collected at predetermined time intervals were analysed for quinine and its major metabolite, 3‐hydroxquinine, using a validated HPLC method. Key findings Administration of quinine plus nevirapine resulted in significant decreases (P < 0.01) in the total area under the concentration–time curve (AUC_T), maximum plasma concentration (C_max) and terminal elimination half‐life (T_1/2β) of quinine compared with values with quinine dosing alone (AUC: 53.29 ± 4.01 vs 35.48 ± 2.01 h mg/l; C_max: 2.83 ± 0.16 vs 1.81 ± 0.06 mg/l; T_1/2β: 11.35 ± 0.72 vs 8.54 ± 0.76 h), while the oral plasma clearance markedly increased (11.32 ± 0.84 vs 16.97 ± 0.98 l/h). In the presence of nevirapine there was a pronounced increase in the ratio of AUC(metabolite)/AUC (unchanged drug) and highly significant increases in C_max and AUC of the metabolite (P < 0.01). Conclusions Nevirapine significantly alters the pharmacokinetics of quinine. An increase in the dose of quinine may be necessary when the drug is co‐administered with nevirapine.