Cytochrome P450 3A Induction Predicts P‐glycoprotein Induction; Part 1: Establishing Induction Relationships Using Ascending Dose Rifampin

Abstract

Drug transporter and cytochrome P450 expression is regulated by shared nuclear receptors and, hence, an inducer should induce both, although the magnitude may differ. The objective of this study was to establish relative induction relationships between CYP3A and drug transporters (P‐glycoprotein (P‐gp), organic anion transporting polypeptide (OATP), and breast cancer resistance protein (BCRP)) or other P450s (CYP2C9 and CYP1A2) using ascending doses of the prototypical pregnane xenobiotic receptor (PXR) agonist, rifampin, to elicit weak, moderate, and strong PXR agonism. Healthy subjects received dabigatran etexilate, pravastatin, rosuvastatin, and a midazolam/tolbutamide/caffeine cocktail before and after rifampin 2, 10, 75, or 600 mg q.d. Unlike CYP3A, only moderate induction of P‐gp, OATP, and CYP2C9 was observed and dose‐dependent induction of P‐gp, OATP, and CYP2C9 was always one drug–drug interaction category lower than observed for CYP3A, even when correcting for probe drug sensitivity. Data from this study establish proof‐of‐concept that P450 induction data can be leveraged to inform on the effect on transporters.

Expanded Physiologically‐Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction

“…Several parameters of pravastatin and pioglitazone were first estimated using the respective observed blood concentration‐time profiles under the control condition ( Table ). Subsequently, the E max values of rifampicin were estimated to be 2.3 for OATP1B and 2.55 for CYP2C8 using the observed blood profiles of pravastatin and pioglitazone after the repeated oral dosing of rifampicin ( Figure a,b and Table ) …”

“…( a,b ) Solid lines and closed circles represent optimized and observed blood concentration‐time profiles, respectively. ( a ) Blood pravastatin profiles after a single oral dose of 20 mg pravastatin before (black) and after repeated oral dosing of 2 mg (blue), 10 mg (green), 75 mg (orange), and 600 mg (red) rifampicin once daily for 10 days . ( b ) Blood pioglitazone profiles after a single oral dose of 30 mg pioglitazone before (black) and after (red) repeated oral dosing of 600 mg rifampicin once daily for 6 days .…”

“…Stepwise optimization was applied to estimate the induction parameter of rifampicin for OATP1B, similar to our previous report . Briefly, pravastatin parameters (absorption rate constant, lag time in intestinal absorption, common scaling factor to in silico tissue/blood concentration ratio values in each tissue, transit rate constant in enterohepatic circulation, and f B CL int,all (= unbound fraction in blood (f B ) × CL int,all )) were first estimated using the blood pravastatin concentration–time profile after a single oral dose of pravastatin (i.e., control condition) . Thereafter, simultaneous optimization for the maximum induction effect (E max ) of rifampicin for OATP1B was conducted using four blood pravastatin profiles after repeated oral dosing of rifampicin (2–600 mg, once daily for 10 days; i.e., DDI condition) .…”

“…In the simultaneous optimization, rifampicin and pravastatin parameters except for rifampicin E max were fixed as shown in Table and Table . The unbound concentration for the half maximum induction effect (EC 50,u ) of rifampicin for OATP1B was set to be equal to that for CYP3A (0.0639 μM), assuming that pregnane X receptor is involved as a key mediator for the induction of both OATP1B and CYP3A (i.e., EC 50,u values reflecting the binding affinity of rifampicin to the pregnane X receptor may be similar for OATP1B and CYP3A) . The E max value of rifampicin for CYP2C8 was estimated via similar stepwise optimization using the blood pioglitazone concentration‐time profiles before and after rifampicin treatment …”

“…Meanwhile, multiple doses of rifampicin reduced the AUC of OATP1B substrates. When 2–600 mg rifampicin was given orally, AUC of pravastatin, which was given 12 hours after the last rifampicin dose, decreased in a rifampicin dose‐dependent manner . Similarly, the AUCR of pravastatin was also 0.69 with multiple doses of rifampicin .…”