Journal of clinical pharmacology
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Abemaciclib, a selective inhibitor of cyclin-dependent kinases 4 and 6, is metabolized mainly by cytochrome P450 (CYP)3A4. Clinical studies were performed to assess the impact of strong inhibitor (clarithromycin) and inducer (rifampin) on the exposure of abemaciclib and active metabolites. A physiologically based pharmacokinetic (PBPK) model incorporating the metabolites was developed to predict the effect of other strong and moderate CYP3A4 inhibitors and inducers. ⋯ The PBPK model predicted 3.78- and 7.15-fold increases in the AUC of the potency-adjusted unbound active species with strong CYP3A4 inhibitors itraconazole and ketoconazole, respectively; and 1.62- and 2.37-fold increases with the concomitant use of moderate CYP3A4 inhibitors verapamil and diltiazem, respectively. The model predicted modafinil, bosentan, and efavirenz would decrease the AUC of the potency-adjusted unbound active species by 29%, 42%, and 52%, respectively. The current PBPK model, which considers changes in unbound potency-adjusted active species, can be used to inform dosing recommendations when abemaciclib is coadministered with CYP3A4 perpetrators.
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To characterize the pharmacokinetics (PK) and exposure-response (E-R) relationship of ustekinumab, an anti-interleukin-12/interleukin-23 (IL-12/IL-23) human monoclonal antibody, in the treatment of moderately to severely active ulcerative colitis (UC), population PK and E-R modeling analyses were conducted based on the data from the pivotal phase 3 induction and maintenance studies in UC patients. The observed serum concentration-time data of ustekinumab were adequately described by a 2-compartment linear PK model with first-order absorption and first-order elimination. ⋯ E-R modeling results suggest that ustekinumab ∼6 mg/kg intravenous induction and 90-mg subcutaneous every-8-week maintenance dose would produce greater efficacy than the 130 mg intravenous induction and the 90-mg subcutaneous every-12-week maintenance regimen, respectively. Our work provides a comprehensive evaluation of ustekinumab PK and E-R in a modeling framework to support ustekinumab dose recommendations in patients with UC.