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To determine if a literature-sourced physiological model for immediate-release (IR) methylphenidate (MPH), with addition of parameters for extended-release (ER) absorption can be adapted for NONMEM analysis to describe extended-release MPH drug products (i.e., Concerta® ER 54 mg tablets and Ritalin-LA® 40 mg capsules) pharmacokinetics (PK) in adults. This semi-physiological model will provide a platform to allow more accurate determination of Cmax in the analysis of methylphenidate plasma data from formulations with complex absorption. Adult reference data for total MPH plasma levels (summation of d- and l- enantiomers) were generated using individual subject parameters from a published NONMEM model for ER MPH (individual subject parameter generated data was used because the true experimental data is proprietary with only the previously-published summary parameters available for public use). The IR physiological model required analysis of both d- and l-MPH enantiomers which were estimated at each time point for the data by calculating the d/l enantiomer ratio from total MPH plasma concentration levels, based upon literature ratio estimates. Absorption was characterized by a fast zero-order and a delayed slow first-order release. Consistent with the literature IR model, two duplicate physiological models were used to describe the d- and l-MPH enantiomers. The mean and variability ratios for the individual subject parameter-generated data/true experimental data were very close to 1.0. The predictive performance of the absorption-modified physiological model and its disposition parameters were demonstrated, as they described both the Concerta® and Ritalin LA® PK and Cmax values very well. The bias was less than 6% for Concerta® peaks while peak 1 for d-Ritalin LA® was 12.9% and peak 2, 7.5%. The IR MPH physiological model, adapted for NONMEM analyses of the ER MPH drug products Concerta® and Ritalin LA® described the individual parameter-generated reference data well for both formulations.

Background: More than 50 % of individuals affected by adverse drug events (ADEs) are older adults. Establishing a drug dosing regimen that balances benefit and risk, and minimizes ADEs in older populations can be challenging. Objective: The aim of this study is to evaluate the use of modeling, simulation, and risk-benefit acceptability methods to establish a drug dosing regimen that balances benefit and risk. Methods: The study population comprised nondiabetic patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) ≥50 years old, who had been on oral olanzapine for ≥2 weeks. We used mixed-effects modeling based on a preexisting pharmacokinetic model to derive clearance estimates, which were then used to determine the olanzapine area under the concentration-time curve (AUC). Subsequently, with multivariate regression and Monte Carlo simulation, we estimated the olanzapine dose corresponding to the benefit-risk AUC breakpoint. Results: The study population (n = 34) was predominantly male (82.3%) and white (67.6%), with a mean age of 54.4 years and treatment duration of 361.8 days. The mean AUC was 747.6 ng h/mL (95% CI = 524.5, 970.7) for the benefit group (n = 16) and 754.1 (95% CI = 505.9, 1002.4) for the risk group (n = 15). The benefit-risk AUC breakpoint was 524.5 ng h/mL and the corresponding oral olanzapine dose that optimizes benefit-risk balance was 17.8 mg/d. Conclusions: Our study introduces a real-world approach for finding the safe drug dosing regimen without extensive exposure of a vulnerable and older population to drugs. Further studies into the use of modeling, simulation, and risk-benefit acceptability methods to enhance geriatric drug safety are needed.

A simulation study was done to determine if 72 h is the most informative sampling duration for bioequivalence (BE) determination in paralleldesigned BE studies with drugs that have half-lives of at least 30 h. The impact of absorption and elimination half-lives on informative sampling was evaluated. Two-treatment parallel-designed BE studies using a one-compartment oral absorption model with half-lives of 30 and 350 h was simulated. Area under the curve (AUC) values were truncated at 12–360 h. Experimental BE data [median time to reach the maximum concentration ( T max ) = 20 h and low clearance = 0.192 L/h) indicated a decrease and then an increase in the intrasubject variability [root mean square error (RMSE)] for truncated AUC as a function of time. Simulations supported these findings with the highest probability of passing the BE confidence interval criteria being between 60 and 96 h, depending on half-life and percent coefficient of variation. The 30-h simulation exhibited a minimum in RMSE at 24-h truncation that continued to increase up to 360 h, whereas the 350-h simulation exhibited a minimum at 60 h, which increased after 96 h. Power curves at the 350-h half-life showed higher probabilities of rejection of BE for true test/reference ratios greater than 0.9. For parallel-designed BE studies, sampling beyond 120 h will not affect the BE decision and therefore is unnecessary. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4337–4346, 2012

Objective This article summarizes the US Food and Drug Administration's (FDA's) review of the New Drug Application for vortioxetine, especially the clinical efficacy and safety data. It emphasizes the issues that were important to the FDA's approval decision, particularly the difference in the effective dose in domestic and foreign studies, and notes several new labeling features, specifically, description of time course of treatment response and detailed sexual dysfunction evaluation. Data sources The data sources were the original raw data sets for all clinical trials included in the development program for vortioxetine, as well as the sponsor's original analyses of these data. Data were available from 51 human trials involving vortioxetine, and included a total of 7,666 healthy volunteers and patients with a diagnosis of major depressive disorder (MDD) or generalized anxiety disorder who were exposed to at least 1 dose of vortioxetine for a total of 2,743 patient-years. Results Vortioxetine was effective in treating MDD in the United States at a dose of 20 mg/d. The recommended starting dose is 10 mg once daily without regard to food, with increase to 20 mg/d if the 10 mg/d dose is tolerated. For patients who do not tolerate 20 mg/d, 10 mg/d can be used and 5-mg/d dose can be considered. Vortioxetine can be discontinued abruptly, but it is recommended that doses of 15 mg/d or 20 mg/d be reduced to 10 mg/d for 1 week prior to full discontinuation to avoid potential withdrawal symptoms. Although the non-US maintenance study showed that maintenance doses of 5 to 10 mg/d were effective, a clinical judgment needs to be made to decide the maintenance dose in the United States. The applicant has agreed to conduct a US maintenance dose-response study covering the US-approved dose range. Vortioxetine's adverse event profile is similar to that of other selective serotonin reuptake inhibitors (SSRIs). Nausea is the most common adverse event and is dose dependent. No dose adjustment is needed based on age, gender, or the presence of renal or mild to moderate hepatic impairment. The maximum recommended dose is 10 mg/d in known cytochrome P450 2D6 poor metabolizers. Conclusions Vortioxetine is a new treatment for MDD, and its adverse event profile is similar to that of other SSRIs.

The usefulness of a limited sampling method (LSM) to determine the bioequivalence of highly variable drugs with long half-lives was investigated. The LSM uses multiple linear regression of observed drug plasma concentrations versus area under the curve (AUC) or C(max) (peak plasma concentration) to obtain a best set of coefficients, concentration times and intercept based upon the regression coefficient, R(2), to predict the selected pharmacokinetic parameter (i.e. AUC or C(max)). The LSM, used successfully in clinical settings, has also been suggested for data analysis of in vivo bioequivalence studies. Because the method has not yet been thoroughly tested under many conditions likely to be encountered in bioequivalence studies, a further investigation of the method's applicability to bioequivalence determination was undertaken. In the present study, training and test data sets incorporating various levels of intrasubject variability in clearance (CL) with different ratios for fraction absorbed (Fa) of test and reference drug formulations were used to further evaluate the applicability of the limited sampling method (LSM) to the evaluation of bioequivalence for drugs with long half-lives of elimination. Both simulated (a one-compartment pharmacokinetic (PK) model with first-order elimination) and experimental data were used in the study. The results indicated that the determination of bioequivalence using the LSM was significantly influenced by the ratio of Fa(test)/Fa(reference) and by the level of intrasubject error (variability) in CL. Therefore, use of the LSM to determine bioequivalence of drugs with long half-lives and highly variable in CL seems suitable only for formulations that have point estimates of Fa(test)/Fa(reference) within the range of 0.9-1.10. Because the Fa ratio range would have to be verified through use of observed data obtained from a pilot study, the practical utility of the LSM in the determination of bioequivalence would be severely limited.

In bioequivalence studies, the first blood or plasma sample taken after dosing sometimes yields a higher assayed drug concentration than any samples drawn thereafter. This circumstance ('first C(max)' or 'FCM'), is usually considered undesirable, since a 'true C(max)' requires that the sampled concentrations immediately preceding and immediately after the 'true C(max)' concentration should be lower than the 'true C(max)' concentration. Therefore, a question arises whether the presence of FCM in a bioequivalence study affects the power and accuracy of the computed statistical confidence interval (CI) for C(max). This study examines what effect, if any, the inclusion or exclusion of FCM data has on the statistical power and accuracy of the 90% CI computed for C(max) in the analysis of results for in vivo bioequivalence studies. Actual experimental study data as well as data from simulated studies were evaluated. In the simulated studies, up to half of the study subjects exhibited FCM, and various levels of intrasubject variability were incorporated into the absorption rate constant. The two one-sided tests procedure was used to assess equivalence of C(max) for the test versus reference products when either a complete set of C(max) data was analysed (designated 'CC(max)'), which included subjects with FCM profiles; or a truncated set of data was analysed (designated 'TC(max)'), that excluded all subjects with FCM. The results showed that the CC(max) metric had greater statistical power and comparable or greater statistical accuracy compared to TC(max) for both bioequivalent and non-bioequivalent drug product formulations. Even when up to 50% of the study subjects had FCM, the power and accuracy of the 90% CI for rate of absorption (i.e. C(max)) was not significantly affected. Consequently, this study shows that, in the analysis of data from conventional in vivo bioequivalence studies, the inclusion of 50% of the subjects exhibiting FCM does not greatly impact the statistical results obtained for C(max). Published in 2000 by John Wiley & Sons, Ltd.

Purpose. Simulated pharmacokinetic (PK) studies were done to determine the effect of intrinsic clearance (CLINT) on the probability of meeting bioequivalence criteria for extent (AUC) and rate (Cmax) of drug absorption when the absorption rate and fraction absorbed (F) were formulated either to be equivalent or to differ by 25%.

Purpose. To compare the applicability and accuracy of truncated area (AUCt; where t represents truncated time) versus area to the last quantifiable time point [AUC(O-T)] for assessing bioequivalence. Drugs with either very low or very high intra-subject variability in clearance (CL) were selected for study. Clearance variability was defined by the number of subjects with a quantifiable plasma value (Cp) at each collection time from 24 hrs to last collection time (T).

Purpose. Two methods to confirm attainment of steady-state conditions in multiple-dose bioequivalence studies are described and evaluated: (1) the Cmin method and (2) the Area Below the Cmin plasma-concentration-versus-time-curve method (ABCM method). Methods. Cmin Method—After repetitive drug administration to presumed steady-state, successive trough, or Cmin, values are evaluated to determine if they are equal. ABCM Method—The ABCM of successive doses from dose two to presumed steady-state [ABCM(ss)] are divided by the ABCM for the first dose, ABCM(t), to give ABCM(ss)/ ABCM(t)=R, which describes the increase in ABCM(n) with successive doses. The quantity, R, is then divided by an accumulation ratio to render the value independent of intra-subject clearance differences. Monte Carlo simulations were done to test the effects of data error and slow-clearing subpopulations on the method's performance. Data from multiple-dose bioequivalence studies were evaluated using confidence intervals for both methods to determine how well each predicted steady-state for immediate-release and controlled-release drug products. Results/Conclusions. The Cmin method more accurately predicted the attainment of steady-state conditions for immediate-release formulations compared to the ABCM method. Conversely, the ABCM procedure more accurately predicted the attainment of steady-state conditions for controlled-release formulations compared to the Cmin method. The simulation results were further supported by the experimental data.

Investigate the performance of partial area under the drug concentration-time curve (PAUC) metrics (0-3 h) and (3-24 h), for Concerta, Ritalin LA and Focalin XR (different Methylphenidate modified-release formulations). The metrics have been chosen as additional BE metrics for Ritalin LA by the FDA to establish BE for these products due to the early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD).Two-stage analysis was performed on plasma data for the methylphenidate modified-release products. Simulations using the fitted parameters determined how changes in fast absorption rate constant k0fast, and slow absorption rate constant KAslow affected curve shape and BE determination using Cmax, AUCINF and PAUC.Sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in k0fast and Kaslow were product dependent. Focalin XR mean PAUC(test)/PAUC(reference) ratios for PAUC0-3 h and PAUC3-24 h were most responsive to changes in k0Fast and Kaslow than Concerta and Ritalin LA. The PAUC(test)/PAUC(reference) ratios for (0-3 h) were not responsive to changes to Kaslow. Concerta PAUC (3-24 h) ratios were responsive to changes in Kaslow at ratios less than 1.Response to PAUC(0-3 h) in the formulations was greater for k0fast than was PAUC(3-24) to changes in KAslow.

Background : The pharmacokinetics of dacarbazine (DTIC), which has been shown to be an effective therapeutic agent against metastatic melanoma, has not been extensively studied. However, to improve the clinical use of the drug, more information on the kinetics is required. Methods : A pharmacokinetic study was undertaken in six patients with melanoma of an extremity who were undergoing hyperthermic isolation perfusion with DTIC in order to understand better its clinical pharmacokinetics. Plasma was sampled from the arterial and venous lines of an extracorporeal pump during the perfusion with the systemic vein and urine sampled postperfusion. Samples were analyzed for DTIC, 2-azahypoxanthine (2-AZA), and aminoimidazole carboxamide (AIC). 99m Tc (Technetium) human serum albumin (HSA) was used in the perfusion circuit to monitor the crossover of the perfusate into the systemic circulation during the procedure. The data were analyzed using a compartmental model of sampled body compartments incorporating the isolated extremity. Results : High tissue DTIC levels were maintained throughout the perfusion, whereas in the systemic circulation, plasma DTIC concentrations, when observed, were 40-100-fold less than those in the perfusate. Almost 70% of the DTIC administered was not recovered in the perfusate after the washout of the extremity. Conclusions : High levels of DTIC can be maintained in an extremity (i.e., arm or leg) during perfusion.

Purpose. A Monte Carlo simulation study was done to investigate the effects of high intrasubject variation in clearance (CL), and volume of distribution (V) on the calculation of the 90% confidence interval (CI) for Cmax for single dose and multiple dose studies. Methods. Simulations were done for both immediate release and sustained release scenarios. The simulated data were compared with clinical data from bioequivalence studies performed on indomethacin and verapamil. Results. Previous reviews and simulations have shown that the probability of failure for the Cmax for single dose studies was always greater than that for multiple dose studies. However, the results for the simulated scenarios currently investigated indicate that if intrasubject (period-to-period) variation in CL and V is high (% CV's above 25%, and 12%, respectively), multiple dose studies can exhibit a higher probability of failure for Cmax than do single dose studies. Furthermore, Cmax values from studies performed with a sustained release scenario are more sensitive to changes in Ka, CL, and V than are results of studies on immediate release products. As an example, the probability of failure for immediate release products in simulated single dose studies is about 11% and 21% when the mean difference in Ka is 10% and 20%, respectively; while, the probability of failure for multiple dose studies is about 36% regardless of the difference in Ka. The corresponding values for the probability of failure for sustained release products were 25%, 53% for single dose studies and 39% for multiple dose studies. The simulations also indicate that changes in the fraction absorbed have a greater effect on the estimation of Cmax in multiple dose regimens than in single dose studies. Conclusions. The results from these investigations indicate that multiple dose studies do not necessarily always reduce variability in Cmax.

Simulations were conducted to address the question of whether metabolite data are required for bioequivalence evaluation of immediate release formulations with drugs exhibiting linear pharmacokinetics and first-pass effect. Plasma level-time profiles were generated for parent drug and metabolite using relevant rate constants obtained from a bivariate normal distribution and designated random error. Simulation results showed that the need for metabolite data (Cmax) in the assessment of bioequivalence depends on the relative variability between the absorption process of the drug and first-pass route for metabolite(s). The importance of metabolite Cmax data in the evaluation of rate of availability is clearly demonstrated for drugs with a high degree of intra-subject variation in the first-pass metabolism compared to the absorption process of the drug. Under such conditions, a wider confidence interval was found for the metabolite rather than parent drug. Opposite results were obtained when the intra-subject variance was high for drug absorption relative to first-pass effect. Discrepancies were observed for the scenarios in which the elimination pathway of the metabolite is more variable than the absorption process of the drug. The simulation results were in agreement with real bioequivalence data. It is thus recommended that, in the absence of the information on the relative variability of absorption and first-pass process, both parent drug and metabolite data be included for documentation of bioequivalence, should the metabolite(s) play an important role in the determination of efficacy and safety of the drug.

Historically, regulatory assessment of bioequivalence (BE) has relied upon the comparison of rate and extent of drug absorption between products (1). For drugs intended to be absorbed and systemically delivered to the site(s) of activity, this is generally achieved by measuring drug concentrations in an accessible biological fluid such as blood plasma. Typically, a single-dose, two-treatment, two-period, crossover design study is conducted in a limited number of healthy volunteers under fasting and fed conditions. Two products are deemed bioequivalent if the 90% confidence intervals of the geometric mean test/reference ratios for the pharmacokinetic (PK) parameters maximum plasma concentration, for rate (Cmax); area under the plasma concentration–time curve, for extent (AUC0-t); extrapolated total area under plasma curve to time infinity (AUC∞) fall within the limits of 80–125% (2). For the majority of systemically active drug products reviewed by the Office of Generic Drugs (OGD), the “traditional” metrics, AUC and Cmax, are effective measures of BE. However, in cases where rapid onset of action as well as controlled duration of effect is needed for drug efficacy, a partial AUC metric (pAUC, a portion of the total AUC) may be needed to ensure therapeutic equivalency (3). For example, Ritalin LA® (methylphenidate HCl) is a mixed modified release (MMR) formulation designed to release a bolus of drug for rapid onset of activity and a delayed bolus of drug to sustain activity throughout the day (4). Ritalin LA® capsules contain half the dose as IR beads and half the dose as enteric-coated, DR beads. The Food and Drug Administration (FDA) currently recommends using two pAUC metrics, in addition to AUC∞ and Cmax, to assess BE of generics to Ritalin LA® (see Fig. 1) (5). To better understand the rationale for using pAUC metrics for Ritalin LA®, as well as the selection of the time intervals used for pAUCs, it is important to understand the interplay of the MMR drug release profile with the pharmacodynamic (PD) and PK properties of methylphenidate (MPH) (6). Fig. 1 The first (early) pAUC metric, AUC0-T, compares test and reference systemic exposure responsible for early onset of response, while the second (late) pAUC metric, AUCT-t, compares test and reference systemic exposure responsible for sustaining the response ... MPH is used to treat attention deficit disorder (ADD) and has a short half-life (2 h) and duration of efficacy (2–3 h) (4). According the FDA labeling, MPH MMR formulations (Ritalin LA®, Concerta®, and Metadate CD®) can be taken once a day, providing rapid onset of action in the morning and coverage during the day. MPH’s clinical effects can be assessed using the SKAMP (Swanson, Kotkin, Alger, M-Fynne, and Pelham) ratings (7). Thus, the time course of clinical outcome in ADD patients can be related to MPH pharmacokinetics by a PK/PD model. A PK/PD model was developed by comparing the time course of clinical (SKAMP) response to methylphenidate plasma concentrations following dosing with Concerta® and Metadate CD®. The model showed that clinical superiority is expected at any point in time for the formulation with the highest methylphenidate concentration (8). Therefore, a generic of Ritalin LA could potentially have an AUC and Cmax comparable to the RLD, but not be therapeutically equivalent due to differences in the time concentration profile. As previously stated, two products are deemed bioequivalent if the 90% confidence intervals of the test/reference ratios for Cmax, AUC0-t, and AUC∞ fall within the BE limits of 80–125%. The parameter Tmax (the time of the peak plasma concentration) is also evaluated for similarity by the OGD, but not subject to statistical evaluation. If Tmax differs markedly between the test and reference products, OGD consults the relevant clinical division in the Center for Drug Evaluation and Research to determine whether such differences could result in a lack of therapeutic equivalence. However, the observed Tmax in patients taking Ritalin LA® does not occur in some subjects until the MPH from the DR portion of the formulations is being absorbed. Thus, Tmax will not always provide information about whether a generic of Ritalin LA will provide the same onset of activity as the RLD (1,9). In contrast, the PK parameters of the MPH IR products (e.g. Ritalin®) are characteristics of a single release phase. We used the PK data from the IR MPH formulation to have an unbiased estimate of the Tmax of the IR component of the MMR formulation (10). The Tmax of MPH occurs at 2 h, which is also the time at which the peak PD effect of the early portion of Ritalin LA® is observed (4). We analyzed the PK data from FDA submissions and for IR only MPH products Tmax is about 2 ± 0.5 and 3 ± 0.5 h under fasting and fed conditions, respectively. Generally, approximately 95% of observations fall within two standard deviations of the mean. Therefore, pAUCs calculated to 3 h (pAUC0-3) in a fasting BE study and 4 h (pAUC0-4) for a fed BE study should ensure that 95% of the subjects should achieve their desired therapeutic response. Likewise, applying pAUC3-t and pAUC4-t to fasting and fed BE studies, respectively, should ensure that two products are therapeutically equivalent over the later part of the daily dosing interval. The variability of the early pAUC is higher than that of Cmax and AUC∞ under fasting and fed conditions, but reasonable for use in an equivalence test. In conclusion, the use of two pAUCs metrics along with the AUC∞ and Cmax will ensure that the pharmacokinetic profiles and clinical effects of generics of Ritalin LA® are sufficiently similar to the brand name drug. For Ritalin LA®, the first (early) pAUC metric is designed to ensure that 90–95% of the subjects have achieved the optimal early onset of response, while the second (late) pAUC metric assesses the response due to the DR portion of the formulation.

Methylphenidate modified-release products produce early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD). Standard bioequivalence (BE) criteria cannot be applied to these products. The performance of partial area under the drug concentration-time curve (PAUC), Cmax and AUCINF to assess BE were independently evaluated for two products. A two-stage analysis was performed on plasma data for two methylphenidate modified-release products (Product 1 and 2). Simulations using the fitted parameters determined how changes in fast absorption rate constant (K0Fast) and fraction available (F1) affected curve shape and BE determination using Cmax, AUCINF and PAUC. The sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in K0Fast(test) are product dependent. Product 1 mean PAUC(test)/PAUC(reference) ratios for PAUC0-4h are more responsive to both decreases and increases in K0Fast(test) than Product 2. Product 2 showed a greater response in the mean PAUC(test)/PAUC(reference) ratio for PAUC0-4h when the K0Fast(test) is decreased and less response as the value is increased. PAUC estimated curve shape is sensitive to changes in absorption and are product specific, and may require a new PAUC metric for each drug. A non-product specific metric to assess curve shape is warranted.

The purpose of this study was to evaluate the relative performance and usefulness of single dose (SD) and multiple dose (MD) regimens for bioequivalence (BE) determination. Drugs such as indomethacin, procainamide, erythromycin, quinidine, nifedipine were tested for BE under SD and MD dose regimens. Drugs characterized by low accumulation indices (AI) showed virtually no change in the 90% confidence interval (CI) of AUC and CMAX upon multiple dosing. On the other hand, drugs with higher AI appeared to have smaller CI at steady-state. For example, the CI range of AUC and CMAX of quinidine (AI of 1.54) decreased from 26 to 12 and from 22 to 12, respectively, upon multiple dosing. A Monte Carlo simulation study of SD and MD bioequivalence trials was performed. The probability of failing the bioequivalence test was evaluated for several situations defined by different levels of variability and correlation in ka constants, presence or absence of inter- and/or intra-individual variability in clearance (CL) and volume of distribution (V), and different degrees of accumulation. All the possible combinations of these factors were tested with SD and MD study designs. All simulations used 1000 data sets with 30 subjects in each data set for a total of 144 unique designs (total of 144,000 simulations of bioequivalence trials). Upon multiple dosing, narrowing of CI ranges was observed for drugs simulated to have high AI, high variability and a large difference in absorption constants (ka) between test and reference formulations. The mean AUC and CMAX CI ranges for this situation decreased from 15 to 6 and from 16 to 10, respectively, in going from SD to MD design. Thus, there was concordance between simulated and experimental data. The probability of failing the bioequivalence test is shown to dramatically decrease upon multiple dosing due to the changes (range and shift) in the confidence interval.

Objective: To determine if 72 hours is the most informative sampling duration for the bioequivalence (BE) determination for drugs with half-lives > 30 h when using a parallel study design. Methods: Two-treatment parallel-designed BE studies were simulated. A one-compartment oral absorption model with half-lives of 30 h and 350 h (clearance = 0.224 or 0.019 L/h), distribution volume = 9.7 L, and inter-subject variability for clearance of 75-250% was simulated. The test/reference ratio for fraction available was investigated at 1.0 and 1.25, while the rate constants for absorption (Ka) were simulated at a test/reference ratio of 1 and 4. AUC values truncated at 12-360 h were calculated. Experimental parallel BE studies drugs were also investigated. Key findings: Experimental BE data indicated a decrease and then an increase in the root mean square error (RMSE) or variability as a function of time. Simulations supported these findings with the highest probability of passing the CI being between times 24 and 120 h depending on Ka, half-life, and inter-subject variability. Based on this work, a reduction in the sampling duration of parallel-designed BE studies is recommended. Experimental BE data indicated a decrease and then an increase in the RMSE. The 30-h half-life simulations exhibited a minimum in RMSE that rose to a plateau at 350 h. There was an increase in the probability of rejecting BE with longer sampling times for the 30-h simulations showing a maximum near 300 h while the 350-h half-life simulations showed no maximum. Conclusion: For parallel-designed BE studies, sampling beyond 120 h will not change the BE decision and therefore is unnecessary.

Applying a comedication (COMD) covariate to apparent clearance (CL(app) = CL/F) is a common practice when using population pharmacokinetics (PopPK) to study metabolism-based drug-drug interactions (DDI). This study evaluates the importance of independently applying COMD to F and CL to account for DDI at the level of first-pass metabolism. A known DDI between single oral doses of the CYP3A substrate midazolam (5 mg) and the inhibitor ketoconazole (400 mg) was simulated using a physiologically based pharmacokinetic simulator SimCyp in virtual subjects. The simulated midazolam data were analyzed by PopPK method under the following scenarios by applying COMD effect to (1) CL(app) only, (2) CL and F, and (3) CL(app) and apparent volume of distribution (V(app) = V/F), assuming V is unchanged. The mean simulated degree of interaction, measured by midazolam AUC ratio with and without ketoconazole (AUCR), was 10.28. Scenario 1 underestimated AUCR. When COMD was independently applied to F and V(app) in scenarios 2 and 3, lower objective function values of the PopPK analysis and more accurate AUCR estimates were achieved. AUCR estimates were also dependent on sampling. The authors conclude that when significant inhibition of the first-pass metabolism of the substrate is anticipated, COMD effects should be applied to both CL and F in PopPK analysis.

We investigated the effects of dose and intrasubject variability (ISV) on bioequivalence (BE) of a parent drug with a single metabolite formed by nonlinear first-pass. A BE simulation was done using a four-compartment model at doses of 17.5, 35.0, and 70.0 mg. ISV was set at either 10% or 20% for clearance and either 20% or 50% for the absorption rate constant, K(a). The ratio of Katest/Kreference was fixed at 1.00 while fraction available ratios, F(test)/F(reference), were varied from 1.00 to 1.25. Results showed the probability of passing the 90% confidence interval (CI) BE requirement for AUC(I), area-under-the-concentration curve to time infinity, and C(max), concentration maximum, were greater for the metabolite than the parent at all F(test)/F(reference) ratios. For the parent, the probability of meeting BE criteria for AUC(I) and C(max) declined from 100% to 60% at the 70 mg dose as the ISV for K(a) increased from 20% to 50% with an increased F(test)/F(reference) ratio. For the metabolite, the probability of meeting BE criteria was above 80% for all doses and ISV values and F(test)/F(reference) ratios less than 1.15. Results show that the parent, reflected absorption, is more informative for determining BE than the metabolite. Clinical data gave a similar result.

The estimation of bioequivalency using metabolite data was investigated for immediate release formulations with drugs exhibiting linear pharmacokinetics and no first-pass effect. This was accomplished by generating parent drug and metabolite plasma level profiles assuming formation and excretion rate-limited pharmacokinetic models with absorption rate constants obtained from bivariate normal distributions and designated random errors. Simulation results indicated that bioequivalence determination using Cmaxof parent drug and metabolite was independent of the metabolite models as evaluated by confidence interval approach. However, a clear difference with respect to the outcome of bioequivalence evaluation arises depending upon the utilization of Cmax values for the parent drug and metabolite. The major reason for this disparity was attributed to the minimal effect of the absorption process for the parent drug on the formation of the metabolite. This phenomenon results in an apparent lower intrasubject variability for Cmax of the metabolite and, in turn, a tighter confidence interval for Cmax of the metabolite in comparison with the parent drug. The simulated results have been found to be in agreement with the bioequivalency data for acetohexamide, allopurinol, procainamide, and sulindac. In all cases, the interval of the 90% confidence limit for Cmax of the metabolite is always smaller than that of the parent drug, regardless of the drug pharmacokinetics and the level of error contained in the data.

The influence of random error and elimination rate on estimates of the area under the curve from zero to time infinity (AUC0–INF) was determined in a simulation study using noninfinity measured AUC values (i.e., AUCTM, area to a measured common sampling time, and AUC0-LAST, area to the last measured sampling time). Further, the extent of absorption of generic danazol, baclofen, and oxazepam was determined using measured methods of estimating area under the curve in bioequivalence studies. The noninfinity AUC estimates and their 90% confidence intervals for the difference in product means were compared for each individual drug. Products chosen fulfilled one of the following three criteria: (1) a high “apparent intrasubject variability” and a half-life greater than 8 hr (danazol); (2) a low apparent intrasubject variability and a half-life less than 4 hr (baclofen); and (3) products exhibiting a low apparent intrasubject variability and a half-life greater than 8 hr (oxazepam). For the simulated data, AUCTM performed best when subjects had similar half-lives (i.e., low variability), which results in AUCTM = AUC0–LAST. On the other hand, AUC0–LAST worked best with a high fractional standard deviation (fsd) and a short elimination half-life (i.e., less than 4 hr). The noninfinity 90% confidence intervals for danazol and oxazepam were inconsistent with those observed at AUC0–INF. However, baclofen, which has a short elimination half-life, exhibited good agreement between the noninfinity and the AUC0–INF 90% confidence intervals. However, across all three drug groups, the comparison based upon the area calculated from time zero to the last quantifiable concentration, AUC0–LAST, consistently provided the best approximation of AUC0–INF.

Although it is widely recognised that measurement of metabolite concentrations is crucial to understanding the clinical pharmacology characteristics of a new molecular entity, a clear consensus on the role of metabolites in the assessment of bioequivalence has never been achieved within the scientific community. However, a regulatory policy for the role of metabolites in bioavailability and bioequivalence has been established by the US FDA. One school of thought believes that the parent drug alone is sensitive to picking up formulation differences, whereas another school of thought believes that establishing bioequivalence criteria on all the species that contribute to safety and efficacy is the only way to ensure the switchability of two products. In this paper, a brief review of the pharmacokinetics of metabolites under different scenarios is presented and the history of the role of metabolites in the assessment of bioequivalence is summarised. Relevant examples from the literature illustrating conflicting opinions on the need for the measurement of metabolites in bioequivalence studies are given. Cases from the literature in which the parent drug is able to meet the 90% confidence intervals while the metabolite(s) fail to do so, and vice versa, are presented to illustrate the difficulty in choosing the pertinent entity to measure. The relevant current US FDA policy and guidelines related to bioavailability and bioequivalence are discussed and contrasted with the rules and regulations applicable in Canada and Europe.

The relationships between post-dosing blood sampling schedules and length of washout interval on the percent of drug carryover into period 2, in a two-treatment, two-period, crossover bioequivalence study was investigated. Observed simulations were done using a two-compartment model with a beta half-life of 100 h, sampling to 200 and 300 h, followed by 1 to 4 washout half-lives. These data were compared with simulations with sampling for 200 and 300 h and no carryover between periods (i.e. true data) and used to establish the per cent carryover. Pseudo-observed concentration period 2 data were also generated for an experimental amiodarone bioequivalence study by adding either 5%, 10% or 50% of the period 2 Cmax value to the observed concentrations of selected subjects (i.e. those with longest half-lives) to give a pseudo-plasma concentration profile. Further investigation via simulation was done by including or excluding subjects with time 0 concentrations of 1%–10% of period 2 Cmax. The simulated data indicated that up to a 3% carryover of AUC into the second period of a bioequivalence study had no effect on the power of the 90% CI for AUC and Cmax. For amiodarone, second period pre-dose drug concentrations equal to as much as 50% of the observed period 2 Cmax value had less effect on the 90% CI (i.e. compared with the true data) for AUC and Cmax than did subject deletion. Copyright © 2003 John Wiley & Sons, Ltd.

The May and June 2001 issues of Pharmaceutical Research contained three articles related to the determination of in vivo Bioequivalence. The articles discussed: (a) the bioequivalence of highly variable drugs, (b) novel metrics for direct comparison of bioequivalence study plasma curves, and (c) the role of a microemulsion vehicle on cutaneous bioequivalence. An analysis of the relationship and potential impact of these articles on their respective areas of bioequivalence will be addressed in this commentary.

The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog’s plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability.

The May and June 2001 issues of Pharmaceutical Research contained three articles related to the determination of in vivo Bioequivalence (1-3). The articles discussed: (a) the bioequivalence of highly variable drugs, (b) novel metrics for direct comparison of bioequivalence study plasma curves, and (c) the role of a microemulsion vehicle on cutaneous bioequivalence.

Complex dosing regimens simulated in the literature using a universal dosing regimen were calculated with a general dosing program developed using the program CONSAM. The program provides a rapid method of calculating nonuniform dosing regimens for up to n = 3 compartments for any linear model. Subject data can also be curve fitted with the program to obtain individual subject estimates to allow for dosage optimization, which is important in a clinical setting. Examples are presented to show the use of the program in optimizing a theophylline regimen, as well as estimation of a new parameter, Cuneq(T), which is defined as the average non-steady-state drug concentration at time t for a drug with an irregular dosing interval.

Amphotericin B lipid complex (ABLC) was recently approved by the Food and Drug Administration for treatment of patients with invasive fungal infections who are intolerant of or refractory to conventional amphotericin B therapy. Little is known, however, about the pharmacokinetics of this new antifungal compound. We therefore investigated the pharmacokinetics of ABLC in comparison with those of conventional desoxycholate amphotericin B (DAmB) in rabbits. The pharmacokinetics of DAmB in a rabbit model were similar to those previously reported in humans. The pharmacokinetics of ABLC differed substantially from those of DAmB. Plasma amphotericin B levels following ABLC administration were 10 times lower than those following administration of an equal dosage of DAmB. The levels of ABLC in whole blood were approximately 40 times greater than those in plasma. The ABLC model differed from the DAmB model by (i) a dose- and time-dependent uptake and return between the plasma compartment and apparent cellular components of the blood-sediment compartment and (ii) time-dependent tissue uptake and return to plasma from serially connected compartments. Following infusion of ABLC, there was a nonlinear uptake into the apparent cellular components of the blood-sediment compartment. This uptake was related to the reciprocal of the integral of the total amount of drug infused (i.e., the more drug infused the greater the fractional uptake between 0.5 and 5 mg/kg of body weight for ABLC). The transfer of drug from plasma to the cellular components of the blood-sediment compartment resulted in initial uptake followed by rapid redistribution back to the plasma. The study describes a detailed model of the pharmacokinetics of ABLC and characterizes a potential role of the cellular components of the blood-sediment compartment in the distribution of this new antifungal compound in tissue.

Two nonlinear pharmacokinetic models were simulated to investigate the relationship between single and multiple dose bioequivalency parameters for drugs such as phenytoin and propranolol which exhibit either saturable elimination kinetics or a capacity limited first pass effect. Mean Tmax, Cmax and area under the plasma-concentration time curve values from 0 to infinity (AUC 0-infinity) were compared after a single and multiple dose(s) of a test or reference drug. The aim was to determine if there were systematic changes in the limits of the single dose confidence interval at steady state that would limit the usefulness of confidence intervals following a single dose in accurately predicting bioavailability following multiple dosing. The 90 per cent confidence interval expressed as a percentage of the reference mean for Tmax, Cmax, and AUC 0-infinity showed model dependent changes from single to multiple dosing in response to the level of data error and changes in absorption. Changes in clearance also seemed to have a marked effect on the observed limits of the single and multiple dose confidence intervals especially for Cmax which showed a characteristic change in the intervals as a function of the clearance ratio. The model used to describe phenytoin had confidence intervals for Cmax and AUC 0-infinity from single to multiple dosing that were similar to that seen for the experimental data. However, the model predictions for Tmax confidence intervals following single and multiple dosing was at variance with the experimental data for formulations A and B.

The relationship between the teratogenicity of EM12, 2-(2,6-dioxopiperiden-3′-yl) phthalimidine, a stable analogue of thalidomide, and zinc status in the maternal animal was investigated using pregnant rats on a low-zinc diet (1 ppm zinc, days 0–14 gestation) as the experimental model. Previous studies with this compound in rats fed a commercial diet at oral doses up to 250 mg/kg per day for three days and intravenous doses up to 10 mg/kg per day for three days failed to produce “typical” thalidomide malformations. However, when a dose of 150 mg/kg was given intraperitoneally to rats on a low-zinc diet, typical thalidomide malformations occurred with an incidence of 57.5%.

The authors have used imidazole carboxamide (DTIC) in vascular isolation and hyperthermic perfusion for melanoma. The regional and systemic toxicity and complications of this procedure were studied in 40 cases with Stage III (15) and Stage I (25) melanoma. Technetium 99m-labelled serum albumin crossover and pharmacokinetic studies were done simultaneously to see if these correlate with toxicity. Local toxicity on muscles, nerves, skin, and arteries was conspicuously absent despite using dosages of 2 g/m2 (40-45 mg/kg) for the lower extremity and 1.2 g/m2 (24-28 mg/kg) for the upper extremity. Skin and core temperature were raised to 39 degrees C to 40 degrees C. Deep vein thrombosis was noted in three patients. No death or gangrene of the extremities occurred. Local infection was noted in only one patient. Fourteen patients (35%) manifested bone marrow toxicity (leukocyte count of 4000/mm3 or platelets of 100,000/mm3) in the second or third week after perfusion. Severe hematologic toxicity was seen in two instances. Dosages of DTIC greater than 40 mg/kg were associated with toxicity in 65% of the patients. No bleeding complications occurred in seven patients with thrombocytopenia. Measurement of crossover and recovery of radionuclide were not reliable indicators of subsequent systemic toxicity. Perfusion fluid balance data also were of no predictive value. Forty-seven percent of the administered DTIC was recovered in washout fluid. Of this, less than 2% was converted to its metabolites, that is aminoimidazole carboxamide and 2-azahypoxanthine. Thirty-five of 40 patients experienced mild nausea and vomiting. Transient and mild hepatotoxicity was noted in seven patients. It appears that DTIC hyperthermic isolation perfusion is a safe procedure, however, the total dosage should be below 40 mg/kg to avoid hematologic toxicity.

Continuous infusion chemotherapy via hepatic artery using newly available mechanical devices is frequently used to treat hepatic metastases to achieve a high concentration of 5-fluorouracil (5-FUra) in the hepatic circulation while minimizing systemic exposure. We compared four routes of intrahepatic administration to find out the best one in the canine model. To ascertain this data, 5-FUra (30 mg/kg) was given as a continuous infusion over a 3 hr period into either a systemic vein (femoral), portal vein, hepatic artery, or hepatic artery distal to its ligation after hepatic dearterialization. A total of eight dogs were studied. During 5-FUra infusion, concomitant blood samples were taken from the inferior vena cava and hepatic vein at 1, 2, 3, 5, 10, 15, 30, 60, 120, and 180 min. 5-FUra levels were determined in plasma by high-performance liquid chromatography. Blood flow in the portal vein and hepatic artery was measured by an electromagnetic flowmeter. The data described by a multicompartmental model, including the measured flows, had separate hepatic arterial and portal compartments with elimination from each described by linear kinetics. Mean area under the curve values in microgram/ml X min and the ratios of the systemic/hepatic vein areas following 5-FUra infusion via systemic, portal vein, hepatic artery, or hepatic artery after dearterialization routes were: 975/539 (R = 1.80), 939/748 (R = 1.35), 211/454 (R = 0.46), and 562/1,424 (R = 0.39). The results indicated that the administration of 5-FUra via the hepatic arterial route distal to its ligation results in the highest hepatic vein drug levels with the smallest systemic/hepatic vein exposure ratio, followed by intra-arterial route, while systemic and portal vein routes were not nearly as advantageous as the intra-arterial routes.

Moment analysis was utilized in the evaluation of equivalency between test and reference formulations with respect to the rate of absorption for four drugs having different pharmacokinetic characteristics. A confidence interval technique was applied to compare the three relevant absorption parameters, that is, peak plasma concentration (Cmax), time to peak plasma concentration (tmax), and mean absorption time (MAT). Equivalence in the absorption rate of drugs was found to be best evaluated by the combined use of MAT, tmax, and Cmax. Use of these parameters for assessing equivalency requires careful interpretation of the results of statistical analysis as well as appropriate consideration of efficacy and safety issues for individual drugs. In addition, the statistical moment method proves to be useful in the assessment of bioequivalency, particularly for drugs with multiple absorption maxima.

A reusable urinary collection device suitable for quantitative collection of uncontaminated urinary samples from rats without using a metabolism cage has been designed. The device can be attached to the pelvic skin within 5 min with minimum handling and discomfort to the unanesthetized rat using an adhesive. The suitability of this device was investigated by collecting and analyzing urine over a 48-h period following the intraperitoneal injection of [14C]inulin. A two-way crossover study was done with samples from one of the two experiments being collected while the animal was housed in a commercially available metabolism cage equipped to separate urine and feces. The percent of the dose excreted, food and water consumption, and the urinary output were not statistically different for rats housed in the metabolism cages or with the collection device attached. Histopathological examination of the rats revealed no pathology after a 24-h period except minor skin inflammation which occurred both in controls and animals to which the device was attached. These studies demonstrate the comparability of the new urine collection device to a commercially available metabolism cage in the quantitative collection of small (0–7 mL) urine samples with less contamination of the samples from the environment.

The pharmacokinetics of desmosine following a 5 mg intravenous dose was determined in five sheep. The biological half-life (t 1/2 beta) of desmosine varied between 81-489 min. Urinary recovery of unchanged desmosine indicated that the compound is not extensively metabolized and that the primary route of elimination is via the kidney.

In vitro plasma protein binding for phenytoin, meperidine, and bretylium tosylate was affected by the type of preserved human blood used for its estimation. Fresh heparinized plasma and serum gave equivalent fractions bound at the concentrations studied for all three drugs. However, the in vitro plasma binding of phenytoin and meperidine decreased ∼9-50% when estimated in fresh citrated plasma or commercially available lyophylized human serum at the concentration levels investigated. The fraction of bretylium tosylate bound to plasma protein decreased ∼30–40% when estimated in fresh citrated plasma but was unchanged when estimated in the lyophylized human serum.

The pharmacokinetics of atropine (dl-hyoscyamine) was studied in six normal volunteers following a single 1-mg intravenous dose of atropine. Atropine plasma levels were collected for 24 hours and analyzed by radioimmunoassay. Pulse rates were monitored and compared with predose values in each subject. Atropine plasma concentrations were fitted by least-squares regression analysis. The observed maximal increase in pulse rate, at 12 to 16 minutes after the dose, correlated with the maximum predicted tissue levels of atropine based on the computer fit of the plasma atropine concentration-time data. No correlation between the time of maximum response and atropine plasma concentrations was observed. The average half-life of atropine was 4.125 hours. This data may be used to design a multiple-dosing regimen for intravenous atropine in patients.

Objective Develop and validate particular, concrete, and abstract yet plausible in silico mechanistic explanations for large intra- and interindividual variability observed for eleven bioequivalence study participants. Do so in the face of considerable uncertainty about mechanisms. Methods We constructed an object-oriented, discrete event model called subject (we use small caps to distinguish computational objects from their biological counterparts). It maps abstractly to a dissolution test system and study subject to whom product was administered orally. A subject comprises four interconnected grid spaces and event mechanisms that map to different physiological features and processes. Drugs move within and between spaces. We followed an established, Iterative Refinement Protocol. Individualized mechanisms were made sufficiently complicated to achieve prespecified Similarity Criteria, but no more so. Within subjects, the dissolution space is linked to both a product-subject Interaction Space and the GI tract. The GI tract and Interaction Space connect to plasma, from which drug is eliminated. Results We discovered parameterizations that enabled the eleven subject simulation results to achieve the most stringent Similarity Criteria. Simulated profiles closely resembled those with normal, odd, and double peaks. We observed important subject-by-formulation interactions within subjects. Conclusion We hypothesize that there were interactions within bioequivalence study participants corresponding to the subject-by-formulation interactions within subjects. Further progress requires methods to transition currently abstract subject mechanisms iteratively and parsimoniously to be more physiologically realistic. As that objective is achieved, the approach presented is expected to become beneficial to drug development (e.g., controlled release) and to a reduction in the number of subjects needed per study plus faster regulatory review.