Vangelis Karalis

Bioequivalence of Highly Variable Drugs: A Comparison of the Newly Proposed Regulatory Approaches by FDA and EMA

ABSTRACTPurposeTo explore the comparative performance of the recently proposed bioequivalence (BE) approaches, FDAs and EMAs, by the FDA working group on highly variable drugs and the EMA, respectively; to compare the impact of the GMR-constraint on the two approaches; and to provide representative plots of % BE acceptance as a function of geometric mean ratio, sample size and variability.MethodsSimulated BE studies and extreme GMR versus CV plots were used. Three sequence, three period crossover studies with two treatments were simulated using four levels of within-subject variability.ResultsThe FDAs and EMAs approaches were identical when variability was <30%. In all other cases, the FDAs method was more permissive than EMAs. The major discrepancy was observed for variability values >50%. The GMR-constraint was necessary for FDAs, especially for drugs with high variabilities. For EMAs, the GMR-constraint only became effective when sample size was large and variability was close to 50%.ConclusionsA significant discrepancy in the performances of FDAs and EMAs was observed for high variability values. The GMR-constraint was essential for FDAs, but it was of minor importance in case of the EMAs.

Novel Scaled Average Bioequivalence Limits Based on GMR and Variability Considerations

AbstractPurpose. i) To develop novel approaches for the construction of bioequivalence (BE) limits incorporating both the intrasubject variability and the geometric mean ratio (GMR), and ii) to assess the performance of the novel approaches in comparison to several scaled BE procedures and the classic unscaled average BE. Methods. Plots of the BE limits or the extreme GMR values accepted as a function of the coefficient of variation (CV) were constructed for published and the developed scaled procedures. Two-period crossover BE investigations with 12, 24, or 36 subjects were simulated with assumptions of a CV 10%, 20%, 30%, or 40%. The decline in the percentage of accepted studies was recorded as the true GMR for the two formulations was raised from 1.00 to 1.50. Acceptance of BE was evaluated by published and the developed scaled procedures, and, for comparison, by the unscaled average BE. Results. Two GMR-dependent BE limits are proposed for the evaluation of average BE: i) BELscG1 with Ln(Upper, Lower BE limit) = ±[(5 − 4GMR)0.496s + Ln(1.25)], and ii) BELscG2 with Ln(Upper, Lower BE limit) = ±[(3 - 2GMR)(0.496s + Ln(1.25))], where s is the square root of the intrasubject variance. The range of BE limits becomes narrower as GMR values deviate from unity, and increases with variability. The two new approaches exhibit the highest statistical power at low CV values. At high levels of variability, BELscG1 and BELscG2 show high statistical power, as well as the lowest percentages of acceptance among the scaled methods when GMR = 1.25. The latter becomes more obvious when a large number of subjects is incorporated in the studies. Conclusions. The GMR and CV estimates of the BE study can be used in conjunction with the GMR vs. CV plot for the assessment of average BE. The new approaches, BELscG1 and BELscG2, appear to be highly effective at all levels of variation investigated.

Drug disposition viewed in terms of the fractal volume of distribution

AbstractPurpose. (i) Evaluate the predictive performance of the fractal volume of drug distribution, vf, (Pharm. Res.18, 1056, 2001), (ii) develop the concept of the fractal clearance, CLf, which is the clearance analogue of vf, (iii) examine the utility of CLf in allometric studies, (iv) develop allometric relationships for the elimination half-life, t1/2, and (v) evaluate the use of vf and CLf in predicting the volume of drug distribution, Vap, clearance, CL, and elimination half-life, t1/2. Methods. Estimates for vf of various drugs were obtained and correlated with body mass using data only from animal species. A comparison was made between the predicted and actual vf values for humans. For a variety of animal species CLf values were estimated from the equation:

Multivariate statistics of disposition pharmacokinetic parameters for structurally unrelated drugs used in therapeutics.

CL_f = \frac{{v_f }}{{V_{ap} }}CL

Safety and pharmacokinetics of oseltamivir for prophylaxis of neonates exposed to influenza H1N1.

The allometric equations developed using CLf were compared with other allometric approaches. Allometric equations were also developed for t1/2 were found to be close to 0.25. Conclusion. The predictive ability of vf is high; predictions for Vap based on vf values are better than the current approaches. CLf expressed a good behavior both in prospective and retrospective analysis. The allometric exponents, 0.75, 0.25 for CLf and t1/2, respectively, agree with the theoretical expected values.

Quantitative structure-pharmacokinetic relationships for disposition parameters of cephalosporins.

Purpose(1) To develop novel scaled bioequivalence (BE) limits with levelling-off properties based solely on variability considerations and (2) to evaluate their performance in comparison to the classic unscaled BE limits 0.80–1.25, the expanded BE limits 0.75–1.33 and the recently proposed Geometric Mean Ratio (GMR)-dependent scaled BE limits BELscW (Karalis et al., Eur. J. Pharm. Sci., 26:54–61, 2005).Materials and MethodsTwo model functions were used to ensure the gradual change of the BE limits from a starting value towards a predefined plateau value. Plots of the new BE limits and extreme GMR values ensuring BE as a function of the coefficient of variation (CV) were constructed. Two-period crossover BE studies with 12, 24, or 36 subjects were simulated assuming CV values from 10 to 60%. Power curves were constructed by recording the percentage of accepted BE studies as the true GMR was raised from 1.00 to 1.50. The percentage of the true GMR within the simulated BE limits vs. true GMR was used to evaluate the estimation accuracy of the scaled methods.ResultsDepending on the parameters’ values of the model functions, the scaled BE limits exhibit different performance. Four new scaled BE limits, showing favourable performance for the evaluation of average BE are presented. At low variability levels two of the novel BE limits show similar performance to the 0.80–1.25 criterion, while the other two (as expected from their design) appear to be less permissive. At high CV values (30, 40%) all new BE limits exhibit much higher statistical power than the 0.80–1.25 criterion. They show almost identical behavior with the expanded 0.75–1.33 limits and appear to be less permissive than BELscW. Finally, the percentage of the true GMR within the simulated BE limits vs. true GMR shows a sharp decline. Due to the absence of the GMR factor in the model functions a more accurate estimation of the new scaled BE limits, compared to BELscW, is observed.ConclusionsThe new scaled BE limits appear to be highly effective at all levels of variation investigated and present satisfactory estimation accuracy.

Keeping a critical eye on the science and the regulation of oral drug absorption: A review

AbstractPurpose. To explore the quantitative structure pharmacokinetic relationships of the disposition parameters: clearance (CL), apparent volume of drug distribution (Vap), fractal clearance (CLf), and fractal volume (vf) for 272 structurally unrelated drugs used in therapeutics. Methods. Literature data were used for CL and Vap whereas CLf and vf were estimated as described previously (Pharm. Res. 18, 1056, 2001 and 19, 697, 2002). A variety of molecular descriptors expressing lipophilicity, ionization, molecular size and hydrogen bonding capacity were estimated using computer packages. The data were analyzed using multivariate statistics. For each disposition parameter (CL, Vap, CLf, vf) PCA (principal component analysis) and PLS (projection to latent structures) were applied to the total set of data as well as to subsets of data. Results. Drugs were divided into two classes (I and II) according to their vf/Vap ratio. Class I comprises 131 drugs with vf/Vap>1, whereas class II 141 drugs with vf/Vap < 1. After initial PLS analysis, class I was subdivided in subclusters I a (30 drugs) and I b (101 drugs). It was found that Ia included mostly acidic drugs with high protein binding, whereas class II comprises mainly basic, lipophilic compounds. No correlation was found between CL, Vap, CLf and the used descriptors. Adequate PLS models were derived for vf considering subclusters Ia, Ib and class II separately. The low vf values of class Ia drugs were affected negatively from molecular size descriptors and non-polar surface area. For class Ib drugs with intermediate vf values, apparent lipophilicity contributed positively, although molecular size descriptors and polarity were inhibitory factors. The high vf values of class II drugs were positively dependent on intrinsic lipophilicity and increased basicity, whereas polarity entered with negative contribution. Conclusions. The parameters Vap, CL, and CLf fail to reflect the physicochemical properties of drugs. The transformation of Vap values to vf is the underlying cause for the valid models for vf. These models allow a global consideration of molecular properties (lipophilicity, ionization, molecular size, polar surface area) which govern the distribution of drugs in the human body. The present study provides additional evidence for the physiologically sound concept of vf.

Pharmacodynamic considerations in bioequivalence assessment: comparison of novel and existing metrics.

AbstractPurpose. To develop the physiologically sound concept of fractal volume of drug distribution, vf, and evaluate its utility and applicability in interspecies pharmacokinetic scaling. Methods. Estimates for vf of various drugs in different species were obtained from the relationship: