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The article focuses on advocating for the nationwide authorization of licensed US pharmacists to prescribe oral contraceptives (OCs) based on their safety and efficacy. Topics include the endorsement of pharmacist-prescribed OCs by the American College of Clinical Pharmacology (ACCP), the evolution of OC formulations, and the training recommendations for pharmacists regarding OC prescription based on US Medical Eligibility Criteria (US MEC) for contraceptive use.

Co‐administration of clesacostat (acetyl‐CoA carboxylase inhibitor, PF‐05221304) and ervogastat (diacylglycerol O‐acyltransferase inhibitor, PF‐06865571) in laboratory models improved non‐alcoholic fatty liver disease (NAFLD)/non‐alcoholic steatohepatitis (NASH) end points and mitigated clesacostat‐induced elevations in circulating triglycerides. Clesacostat is cleared via organic anion‐transporting polypeptide‐mediated hepatic uptake and cytochrome P450 family 3A (CYP3A); in vitro clesacostat is identified as a potential CYP3A time‐dependent inactivator. In vitro ervogastat is identified as a substrate and potential inducer of CYP3A. Prior to longer‐term efficacy trials in participants with NAFLD, safety and pharmacokinetics (PK) were evaluated in a phase I, non‐randomized, open‐label, fixed‐sequence trial in healthy participants. In Cohort 1, participants (n = 7) received clesacostat 15 mg twice daily (b.i.d.) alone (Days 1–7) and co‐administered with ervogastat 300 mg b.i.d. (Days 8–14). Mean systemic clesacostat exposures, when co‐administered with ervogastat, decreased by 12% and 19%, based on maximum plasma drug concentration and area under the plasma drug concentration–time curve during the dosing interval, respectively. In Cohort 2, participants (n = 9) received ervogastat 300 mg b.i.d. alone (Days 1–7) and co‐administered with clesacostat 15 mg b.i.d. (Days 8–14). There were no meaningful differences in systemic ervogastat exposures when administered alone or with clesacostat. Clesacostat 15 mg b.i.d. and ervogastat 300 mg b.i.d. co‐administration was overall safe and well tolerated in healthy participants. Cumulative safety and no clinically meaningful PK drug interactions observed in this study supported co‐administration of these two novel agents in additional studies exploring efficacy and safety in the management of NAFLD. [ABSTRACT FROM AUTHOR]

PF‐05212377 (SAM760) is a potent and selective 5‐HT6 antagonist, previously under development for the treatment of Alzheimer's disease. In vitro, PF‐05212377 was determined to be a P‐gp/non‐BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF‐05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (Cbu/Cpu) of 0.05 in rat and 0.64 in non‐human primates (NHP). Based on pre‐clinical evidence, brain penetration and target engagement of PF‐05212377 was confirmed in NHP using positron emission tomography (PET) measured 5‐HT6 receptor occupancy (%RO). The NHP Cpu EC50 of PF‐05212377 was 0.31 nM (consistent with the in vitro human 5HT6 Ki: 0.32 nM). P‐gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non‐human primates and human; brain penetration of PF‐05212377 in humans was postulated to be similar to that in non‐human primates. In humans, PF‐05212377 demonstrated dose and concentration dependent increases in 5‐HT6 RO; maximal 5‐HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC50 of 0.37 nM (which was similar to the in vitro human 5HT6 binding Ki 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF‐05212377, a P‐gp/non‐BCRP substrate. Clinical trial number: NCT01258751. [ABSTRACT FROM AUTHOR]

PF‐05251749 is a dual inhibitor of casein kinase 1 δ/ε under clinical development to treat disruption of circadian rhythm in Alzheimer's and Parkinson's diseases. In vitro, PF‐05251749 (0.3–100 μM) induced CYP3A in cryopreserved human hepatocytes, demonstrating non‐saturable, dose–dependent CYP3A mRNA increases, with induction slopes in the range 0.036–0.39 μM−1. In a multiple‐dose study (B8001002) in healthy participants, CYP3A activity was explored by measuring changes in 4β‐hydroxycholesterol/cholesterol ratio. Following repeated oral administration of PF‐05251749, up to 400 mg q.d., no significant changes were observed in 4β‐hydroxycholesterol/cholesterol ratio; this ratio increased significantly (~1.5‐fold) following administration of PF‐05251749 at 750 mg q.d., suggesting potential CYP3A induction at this dose. Physiologically based pharmacokinetic (PBPK) models were developed to characterize the observed clinical pharmacokinetics (PK) of PF‐05251749 at 400 and 750 mg q.d.; the PBPK induction model was calibrated using the in vitro linear fit induction slope, with rifampin as reference compound (Indmax = 8, EC50 = 0.32 μM). Clinical trial simulation following co‐administration of PF‐05251749, 400 mg q.d. with oral midazolam 2 mg, predicted no significant drug interaction risk. PBPK model predicted weak drug interaction following co‐administration of PF‐05251749, 750 mg q.d. with midazolam 2 mg. In conclusion, good agreement was obtained between CYP3A drug interaction risk predicted using linear‐slope PBPK model and exploratory biomarker trends. This agreement between two orthogonal approaches enabled assessment of drug interaction risks of PF‐05251749 in early clinical development, in the absence of a clinical drug–drug interaction study. [ABSTRACT FROM AUTHOR]