Azithromycin (Zithromax) is an azalide antibiotic that binds to the 50S ribosomal subunit of the susceptible organism and thereby interferes with its protein synthesis. An open-label, randomized, single-dose, 3-way crossover bioequivalence study was conducted to compare the rate and extent of absorption of the azithromycin 250-mg tablet manufactured at Pfizer Dalian (China) and that at Pfizer Barceloneta (United States) under fasted and fed conditions in healthy Chinese subjects.This study aimed to support a generic consistency evaluation program,initiated by the National Medical Products Administration, for evaluating the quality and efficacy of the products manufactured in China. In the study, the withinsubject standard deviation for area under the serum concentration-time profile from time 0 to 72 hours after dosing in the fasted condition was <0.294, and the 90%CI for the ratio was within 80% to 125%; the within-subject SDs for serum peak concentration in the fasted condition, area under the serum concentration-time profile from time 0 to 72 hours after dosing in the fed condition, and serum peak concentration in the fed condition, were all >0.294, with the upper confidence bounds being <0.00, and the point estimates of the ratios being within 80% to 125%. The results support the bioequivalence between azithromycin tablets manufactured in China and the United States in fasted and fed conditions, with both tablets showing an acceptable safety/tolerability profile in the studied population.

This was an open-label, randomized study in healthy Chinese participants to assess the bioequivalence of 2 fluconazole 150-mg capsules under fasted and fed conditions. The study consisted of 2 treatment periods, separated by a 14-day washout period. Thirty-six participants were enrolled, with 18 participants each in the fasted and fed groups. In each treatment period, participants received a single oral dose of the test or reference fluconazole 150-mg capsule. After washout, participants received the alternate treatment. Blood samples for pharmacokinetic analysis were collected from 1 hour before dosing to 72 hours after dosing. The median plasma concentration-time profiles were similar for both treatments under fasted and fed conditions. Bioequivalence of fluconazole between the 2 capsules was demonstrated as 90% confidence intervals of the geometric mean ratios for the maximum plasma concentration and area under the plasma concentration-time curve from time 0 to 72 hours after dosing under fasted and fed conditions were within the acceptable range of 80%-125%. Overall, 7 participants reported at least 1 treatment-emergent adverse event; all were mild in severity. No serious adverse events or deaths were reported. The test fluconazole capsule was bioequivalent to the reference capsule, and a single dose was well tolerated. Clinicaltrials.gov ID: NCT03621072

AimsBrepocitinib is a tyrosine kinase 2/Janus kinase 1 inhibitor being investigated for the treatment of several autoimmune diseases. This study assessed the absorption, distribution, metabolism and excretion of oral brepocitinib, and the absolute oral bioavailability (F) and fraction absorbed (Fa) using a 14C microtracer approach.MethodsThis was a phase 1 open‐label, nonrandomized, fixed sequence, two‐period, single‐dose study of brepocitinib in healthy male participants. Participants received a single oral 60 mg dose of 14C brepocitinib (~300 nCi) in Period A, then an unlabelled oral 60 mg dose followed by an intravenous (IV) 30 μg dose of 14C labelled brepocitinib (~300 nCi) in Period B. Mass balance, pharmacokinetic parameters and safety were assessed.ResultsSix participants were enrolled. Brepocitinib was absorbed rapidly following oral administration. In Period A, total recovery of the oral dose was 96.7% ± 6.3% (88.0% ± 8.0% in urine, 8.7% ± 2.1% in faeces). In Period B, a small fraction (6.0% of the oral dose) was recovered unchanged in urine. F and Fa were 74.6% (90% confidence interval 67.3%, 82.8%) and 106.9%, respectively. Brepocitinib demonstrated an acceptable safety profile and was well tolerated following oral or oral then IV administrations. No deaths, serious adverse events or discontinuations were reported.ConclusionIntestinal absorption of brepocitinib was essentially complete after oral administration, with F ~75%. Drug‐related material recovery was high, with the majority excreted in urine. The major route of elimination of brepocitinib was renal excretion as metabolites, whereas urinary elimination of unchanged brepocitinib was minor.NCT: NCT03770039.

Purpose Ritlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers. Methods In vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively. Results In vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by  ~ 13% and maximum concentration (Cmax) by  ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUCinf and Cmax for CP-I and PDA were also similar regardless of ritlecitinib coadministration. Conclusion Ritlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity.