Summary report of second EUFEPS/AAPS conference on global harmonization in bioequivalence.

The Global Bioequivalence Harmonization Initiative (GBHI) was launched by the Network on Bioavailability and Biopharmaceutics (BABP) under the auspices of European Federation for Pharmaceutical Sciences (EUFEPS) several years ago. Since 2015, EUFEPS in collaboration with the American Association of Pharmaceutical Scientists (AAPS) has organized three international conferences to support global harmonization of regulatory requirements for bioequivalence (BE) assessment. These conferences provided an open forum for pharmaceutical scientists from academia, industry and regulatory agencies to discuss various BE topics at issue. The current report summarizes the discussion of BE issues at the 2nd GBHI conference held in 2016, Rockville, USA. Three important BE topics were discussed at the meeting: (a) prodrugs and compounds with pre-systemic extraction, (b) scaling procedures and two-stage designs, and (c) exclusion of pharmacokinetic data in BE assessment. The presentations and discussions of these issues have enhanced the mutual understanding of scientific background for BE evaluation and further facilitated harmonization of regulatory approaches for establishing BE of multisource drug products.

Population pharmacokinetic drug-drug interaction pooled analysis of existing data for rifabutin and HIV PIs.

OBJECTIVES: Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV PIs and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated TB, with concurrently administered PIs. METHODS: Individual-level data from 13 published studies were pooled and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin) and drug-drug interaction with PIs in healthy volunteers and patients who had HIV and TB (TB/HIV). RESULTS: Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation of the metabolite (increased by 224% in patients), volume of distribution (increased by 606%) and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, clearance was reduced by 35%-76% and volume of distribution increased by 67%-240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of PIs and 280% with ritonavir-boosted PIs. CONCLUSIONS: Given together with non-boosted or ritonavir-boosted PIs, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant PIs and may achieve peak concentrations within an acceptable therapeutic range. Although 300 mg of rifabutin every 3 days with boosted PI achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.

Novel population pharmacokinetic method compared to the standard noncompartmental approach to assess bioequivalence of iron gluconate formulations.

PURPOSE: Iron-containing products are atypical in terms of their pharmacokinetic properties because iron is only removed by plasma sampling and is non-linear. This study aims to present a novel way of assessing the relative bioavailability of two sodium ferric gluconate complex (SFGC) formulations and compare this approach to a standard previously published noncompartmental approach. METHODS: Data were from open-label, randomized, single-dose studies (Study 1 was parallel whereas Study 2 was crossover). Subjects with low but normal iron levels were infused IV SFGC in sucrose by GeneraMedix Inc. and/or Ferrlecit ® Injection (Watson Laboratories Inc.). In Study 1 (n=240), 125 mg was infused over 10 minutes. In Study 2 (n=29), 62.5 mg was infused over 30 minutes. Samples were assayed for total iron (TI) and transferrin-bound iron (TBI) over 36 hours (Study 1) or 72 hours (Study 2) post-dose. Studies 1 and 2 used standard noncompartmental analysis. Study 2 also used population PK (PPK) analyses with ADAPT 5®. The final model predicted SFGC area-under-the-curve (AUCpred) and maximal concentration (Cmaxpred). Analyses of variance was conducted on ln-transformed PK parameters. Ratios of means and 90% confidence intervals (CIs) were estimated. Bioequivalence was demonstrated if values were within 80-125%. RESULTS: For Study 1, ratios and 90% CIs for TI baseline-corrected Cmax and AUC0-36 were 100.4 (96.5 - 104.5) and 99.7 (94.2 - 105.5). For TBI, results for TI baseline-corrected Cmax and AUC0-36 were 86.8 (82.7 - 91.1) and 92.4 (85.6 - 99.7). For Study 2, a multi-compartmental model simultaneously described the PK of TI, TBI and SFGC. Ratios and 90% CIs for SFGC Cmaxpred and AUCpred were 89.9 (85.9 - 94.0) and 89.7 (85.7 - 93.9), while ratios and 90% CI obtained from the noncompartmental analysis of Study 2 did not meet BE criteria because of low power. CONCLUSIONS: Both the standard and PPK modeling approach suggested bioequivalence between the iron products. However, with the PPK method, less subjects were required to meet study objectives compared to the standard noncompartmental approach which required considerably more subjects (29 vs 240).

2011 White paper on recent issues in bioanalysis and regulatory findings from audits and inspections.

The 5th Workshop on Recent Issues in Bioanalysis (WRIB) was organized by the Calibration and Validation Group as a 2-day full immersion workshop for pharmaceutical companies, CROs and regulatory agencies to discuss, review, share perspectives, provide potential solutions and agree upon a consistent approach to recent issues in the bioanalysis of both small and large molecules. High quality, better compliance to regulations and scientific excellence are the foundation of this workshop. As in the previous editions of this significant event, recommendations were made and a consensus was reached among panelists and attendees, including industry leaders and regulatory experts representing the global bioanalytical community, on many 'hot' topics in bioanalysis. This 2011 White Paper is based on the conclusions from this workshop, and aims to provide a practical reference guide on those topics.

Natural health product-drug interactions: a systematic review of clinical trials.

Interactions between natural health products (NHP) and prescription medications are of increasing concern. This paper aims to identify all clinical trials of NHP-drug interactions. To determine the prevalence and outcomes of clinical investigations of NHP-drug pharmacokinetic interactions, electronic databases were searched from inception through March 2004, as well as reference lists from published reports and experts in the field for unpublished studies. Eligible studies were clinical investigations of the interaction between a NHP and the metabolism of a regulated medication in humans. Studies were excluded that only investigated the metabolism of an NHP or examined food-drug or NHP-NHP interactions. Two reviewers selected studies for inclusion and independently extracted data. Forty-seven trials were identified, studying an average of 14 participants/study (95% confidence interval [CI] 11-18), examined drug interactions with 19 different herbal preparations. All trials were pharmacokinetic studies, 41 of healthy volunteers and 6 of patients. Ten different herbal medicines as well as 5 different traditional herbal concoctions were studied. Potentially clinically significant drug interactions were observed with St. John wort (16/24 studies), garlic (2/5 studies), and American ginseng (1 study). Research on NHP-drug interactions is limited in number and scope. With the exception of St. John wort, clinicians and the public do not have information that permits strong inferences about interactions between NHPs and conventional medications.

Milk thistle and indinavir: a randomized controlled pharmacokinetics study and meta-analysis.

OBJECTIVES: To determine whether ingestion of milk thistle affects the pharmacokinetics of indinavir. METHODS: We conducted a three-period, randomized controlled trial with 16 healthy participants. We randomized participants to milk thistle or control. All participants received initial dosing of indinavir, and baseline indinavir levels were obtained (AUC(0-8)) (phase I). The active group were then given 450 mg milk-thistle extract capsules to be taken t.i.d. from day 2 to day 30. The control group received no plant extract. On day 29 and day 30, indinavir dosing and sampling was repeated in both groups as before (phase II). After a wash-out period of 7 days, indinavir dosing and sampling were repeated as before (phase III). RESULTS: All participants completed the trial, but two were excluded from analysis due to protocol violation. There were no significant between-group differences. Active group mean AUC(0-8) indinavir decreased by 4.4% (90% CI, -27.5% to -26%, P=0.78) from phase I to phase II in the active group, and by 17.3% (90% CI, -37.3% to +9%, P=0.25) in phase III. Control group mean AUC(0-8) decreased by 21.5% (90% CI, -43% to +8%, P=0.2) from phase I to phase II and by 38.5% (90% CI, -55.3% to -15.3%, P=0.01) of baseline at phase III. To place our findings in context, milk thistle-indinavir trials were identified through systematic searches of the literature. A meta-analysis of three milk thistle-indinavir trials revealed a non-significant pooled mean difference of 1% in AUC(0-8) (95% CI, -53% to 55%, P=0.97). CONCLUSIONS: Indinavir levels were not reduced significantly in the presence of milk thistle.

The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum.

OBJECTIVE: The objective of this study was to explore the pharmacokinetics of nelfinavir and its active metabolite hydroxy-t-butylamidenelfinavir (M8) during pregnancy and post partum. METHODS: Eleven human immunodeficiency virus type 1-infected pregnant women receiving 1250 mg nelfinavir twice daily were enrolled. Pharmacokinetics of nelfinavir and M8 were assessed over a 12-hour period during pregnancy (median, 32 weeks' gestation; range, 31-36 weeks) and post partum (median, 8 weeks post partum; range, 6-15 weeks). Drug concentrations were analyzed by HPLC coupled to tandem mass spectroscopy, and pharmacokinetic parameters were calculated by use of noncompartmental methods. RESULTS: The median area under the plasma concentration-time curve from 0 to 12 hours (AUC 0-12), the maximal plasma concentration (C max), and the concentration at the end of the dosing interval (C 12) for nelfinavir post partum were 33.5 h . microg/mL, 5.80 microg/mL, and 1.40 microg/mL, respectively. The values for the geometric mean ratio (GMR) (third trimester/post partum) for the nelfinavir AUC 0-12 , C max , and C 12 were 0.76 (90% confidence interval [CI], 0.54-1.06), 0.81 (90% CI, 0.57-1.15), and 0.43 (90% CI, 0.25-0.76), respectively. The GMR values for the M8 AUC 0-12 , C max , and C 12 were 0.32 (90% CI, 0.18-0.55), 0.31 (90% CI, 0.19-0.51), and 0.30 (90% CI, 0.14-0.64), respectively. The median ratio values of the AUC 0-12 of M8 and nelfinavir (M8/nelfinavir) during the third trimester and post partum were 11% and 27%, respectively (GMR, 0.42 [90% CI, 0.33-0.53]). CONCLUSIONS: Nelfinavir exposure was reduced during pregnancy, and the reduction was statistically significant for C 12 . M8 concentrations were about 70% lower during pregnancy compared with post partum, suggesting either induction of hepatic cytochrome P450 (CYP) 3A4 or inhibition of CYP2C19, or both, during pregnancy. Because 8 of 11 women had subtherapeutic nelfinavir trough concentrations during pregnancy, the safety and efficacy of therapeutic drug monitoring should be investigated.

Interaction of St John's wort with conventional drugs: systematic review of clinical trials.

OBJECTIVE: To determine the methodological quality of clinical trials that examined possible interactions of St John's wort with conventional drugs, and to examine the results of these trials. DESIGN: Systematic review. DATA SOURCES: Electronic databases from inception to April 2004, reference lists from published reports, and experts in the field. STUDY SELECTION: Eligible studies were prospective clinical trials evaluating the pharmacokinetic effect of St John's wort on the metabolism of conventional drugs. DATA EXTRACTION: Two reviewers selected studies for inclusion and independently extracted data. DATA SYNTHESIS: 22 pharmacokinetic trials studied an average of 12 (SD 5) participants; 17 trials studied healthy volunteers and five studied patients. Most (17) studies used a "before and after" design; four studies used control groups other than the active group. Three studies randomised the sequence of administration or the participants to study arms or periods; three studies blinded participants or investigators. In 15 trials, investigators independently assayed the herb. Of 19 trials with available plasma data, three found no important interaction (change in area under the curve < 20%) and 17 found a decrease in systemic bioavailability of the conventional drug; in seven studies the 95% confidence interval excluded a decrease of < 20%. CONCLUSION: Clinicians and patients should beware of possible decreases in the systemic bioavailability of conventional drugs when taken concomitantly with St John's wort.

Effect of short-term administration of garlic supplements on single-dose ritonavir pharmacokinetics in healthy volunteers.

AIMS: To evaluate the effect of acute dosing of garlic supplements on the single-dose pharmacokinetics of ritonavir. METHODS: Ten healthy volunteers (five male, five female) were equally randomized in a crossover design to receive 400 mg of a single dose of ritonavir within 10 min after eating breakfast either alone or with 10 mg of Natural Source Odourless Garlic. They received a total of eight doses of garlic extract (2 x 5 mg capsules) taken twice daily for 4 days. Ritonavir and the seventh garlic dose were administered simultaneously. RESULTS: Coadministration of garlic nonsignificantly decreased area under the plasma concentration-time curve (AUC(0, infinity )) by -17% (90% confidence interval (CI), -31% to 0%; range -46% to 68%) and peak plasma concentration of ritonavir by -1% (90% CI, -25% to 31%; range -51% to 136%). CONCLUSIONS: Acute dosing of the garlic capsules over 4 days did not significantly alter the single-dose pharmacokinetics of ritonavir in healthy volunteers. Given the complex effects of both ritonavir and garlic on drug metabolism, the results of our study should not be extrapolated to steady-state conditions, where the possibility of an interaction still needs to be evaluated.

The effect of garlic supplements on the pharmacokinetics of saquinavir.

Herbal therapies are widely used, but there are few data on their interactions with conventional medications. This study evaluated the effect of garlic supplements on the pharmacokinetics of saquinavir. Ten healthy volunteers received 10 doses of saquinavir (Fortovase) at a dosage of 1200 mg 3 times daily with meals for 4 days on study days 1-4, 22-25, and 36-39, and they received a total of 41 doses of garlic caplets taken 2 times daily on study days 5-25. Blood samples were obtained on study days 4, 25, and 39 for determination of saquinavir plasma pharmacokinetic parameters. In the presence of garlic, the mean saquinavir area under the curve (AUC) during the 8-h dosing interval decreased by 51%, trough levels at 8 h after dosing decreased by 49%, and the mean maximum concentrations (Cmax) decreased by 54%. After the 10-day washout period, the AUC, trough, and Cmax values returned to 60%-70% of their values at baseline. Patients should use caution when combining garlic supplements with saquinavir when it is used as a sole protease inhibitor.