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Abstract PF‐06835919, a ketohexokinase inhibitor, presented as an inducer of cytochrome P450 3A4 (CYP3A4) in vitro (human primary hepatocytes), and static mechanistic modeling exercises predicted significant induction in vivo (oral midazolam area under the plasma concentration‐time curve [AUC] ratio [AUCR] = 0.23–0.79). Therefore, a drug–drug interaction study was conducted to evaluate the effect of multiple doses of PF‐06835919 (300 mg once daily × 10 days; N = 10 healthy participants) on the pharmacokinetics of a single oral midazolam 7.5 mg dose. The adjusted geometric means for midazolam AUC and its maximal plasma concentration were similar following co‐administration with PF‐06835919 (vs. midazolam administration alone), with ratios of the adjusted geometric means (90% confidence interval [CI]) of 97.6% (90% CI: 79.9%–119%) and 98.9% (90% CI: 76.4%–128%), respectively, suggesting there was minimal effect of PF‐06835919 on midazolam pharmacokinetics. Lack of CYP3A4 induction was confirmed after the preparation of subject plasma‐derived small extracellular vesicles (sEVs) and conducting proteomic and activity (midazolam 1′‐hydroxylase) analysis. Consistent with the midazolam AUCR observed, the CYP3A4 protein expression fold‐induction (geometric mean, 90% CI) was low in liver (0.9, 90% CI: 0.7–1.2) and non‐liver (0.9, 90% CI: 0.7‐1.2) sEVs (predicted AUCR = 1.0, 90% CI: 0.9–1.2). Likewise, minimal induction of CYP3A4 activity (geometric mean, 90% CI) in both liver (1.1, 90% CI: 0.9–1.3) and non‐liver (0.9, 90% CI: 0.5‐1.5) sEVs was evident (predicted AUCR = 0.9, 90% CI: 0.6‐1.4). The results showcase the integrated use of an oral CYP3A probe (midazolam) and plasma‐derived sEVs to assess a drug candidate as inducer.

Abstract Although rifampin drug–drug interaction (DDI) studies are routinely conducted, there have been instances of liver function test (LFT) elevations, warranting further evaluation. A literature review was conducted to identify studies in which combination with rifampin resulted in hepatic events and evaluate any similarities. Over 600 abstracts and manuscripts describing rifampin DDI studies were first evaluated, of which 30 clinical studies reported LFT elevations. Out of these, 11 studies included ritonavir in combination with other drug(s) in the rifampin DDI study. The number of subjects that were discontinued from treatment on these studies ranged from 0 to 71 (0–100% of subjects in each study). The number of subjects hospitalized for adverse events in these studies ranged from 0 to 41 (0–83.67% of subjects in each study). LFT elevations in greater than 50% of subjects were noted during the concomitant administration of rifampin with ritonavir‐boosted protease inhibitors and with lorlatinib; with labeled contraindication due to observed hepatotoxicity related safety findings only for saquinavir/ritonavir and lorlatinib. In the lorlatinib and ritonavir DDI studies, considerable LFT elevations were observed rapidly, typically within 24–72 h following co‐administration. A possible sequence effect has been speculated, where rifampin induction prior to administration of the combination may be associated with increased severity of the LFT elevations. The potential role of rifampin in the metabolic activation of certain drugs into metabolites with hepatic effects needs to be taken into consideration when conducting rifampin DDI studies, particularly those for which the metabolic profiles are not fully elucidated.