Physiologically‐Based Pharmacokinetic Modeling Approach to Predict Rifampin‐Mediated Intestinal P‐Glycoprotein Induction

Yamazaki, Shinji; Costales, Chester; Lazzaro, Sarah; Eatemadpour, Soraya; Kimoto, Emi; Varma, Manthena V.

doi:10.1002/psp4.12458

Cited by 45 publications

(63 citation statements)

References 47 publications

(127 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In these studies, the duodenal content of P-gp from gut biopsies was highly inversely correlated to digoxin and talinolol systemic exposure, demonstrating the predominant impact on intestinal P-gp [63,64]. These results suggest that three to fourfold increases in intestinal P-gp abundances by P-gp inducers result in maximal effect in reduction of exposure of the P-gp substrate when administered orally [94], given that rifampin appears to be the strongest P-gp inducer studied to date.…”

Section: Rifampinmentioning

confidence: 68%

“…These models have been increasingly used to assess CYP450 enzymemediated DDIs to derive dosing recommendations in lieu of dedicated clinical studies [6,128]. In recent years, examples on the use of PBPK for substrates of OATP, renal transporters, and P-gp have been described [94,128]. For example, talinolol PK were described using a PBPK model that incorporated the saturable kinetics of P-gp in the intestine and adequately described the increased oral bioavailability with higher talinolol doses [129].…”

Section: Interpretation and Practical Implications Of Key Findingsmentioning

confidence: 99%

See 1 more Smart Citation

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

et al. 2020

View full text Add to dashboard Cite

Understanding transporter-mediated drug-drug interactions (DDIs) for investigational agents is important during drug development to assess DDI liability, its clinical relevance, and to determine appropriate DDI management strategies. P-glycoprotein (P-gp) is an efflux transporter that influences the pharmacokinetics (PK) of various compounds. Assessing transporter induction in vitro is challenging and is not always predictive of in vivo effects, and hence there is a need to consider clinical DDI studies; however, there is no clear guidance on when clinical evaluation of transporter induction is required. Furthermore, there is no proposed list of index transporter inducers to be used in clinical studies. This review evaluated DDI studies with known P-gp inducers to better understand the mechanism and site of P-gp induction, as well as the magnitude of induction effect on the exposure of P-gp substrates. Our review indicates that P-gp and cytochrome P450 (CYP450) enzymes are coregulated via the pregnane xenobiotic receptor (PXR) and the constitutive androstane receptor (CAR). The magnitude of the decrease in substrate drug exposure by P-gp induction is generally less than that of CYP3A. Most P-gp inducers reduced total bioavailability with a minor impact on renal clearance, despite known expression of P-gp at the apical membrane of the kidney proximal tubules. Rifampin is the most potent P-gp inducer, resulting in an average reduction in substrate exposure ranging between 20 and 67%. For other inducers, the reduction in P-gp substrate exposure ranged from 12 to 42%. A lower reduction in exposure of the P-gp substrate was observed with a lower dose of the inducer and/or if the administration of the inducer and substrate was simultaneous, i.e. not staggered. These findings suggest that clinical evaluation of the impact of P-gp inducers on the PK of investigational agents that are substrates for P-gp might be warranted only for compounds with a relatively steep exposure-efficacy relationship.

show abstract

Section: Rifampinmentioning

confidence: 68%

Section: Interpretation and Practical Implications Of Key Findingsmentioning

confidence: 99%

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

et al. 2020

View full text Add to dashboard Cite

show abstract

“…5 Subsequent PBPK modeling of the effects of multiple high-dose rifampin on digoxin, talinolol, and dabigatran etexilate ( Table 1) estimated maximal induction of intestinal P-gp within this approximately threefold to fourfold range. 5,6,16 Therefore, it was reasonably assumed that clinical induction of intestinal P-gp by multiple high-dose rifampin represents maximal induction response (strongest clinical PXR activator). Physiologically-based pharmacokinetic modeling could be used to interrogate whether an approximately threefold to fourfold induction of intestinal P-gp impacts the absorption and exposure of likely comedications that are P-gp substrates or an investigational drug with P-gp-limited absorption.…”

Section: Evaluation Of P-gp Induction: Ddi Prediction Approachesmentioning

confidence: 99%

Intestinal P‐gp and Putative Hepatic OATP1B Induction: International Transporter Consortium Perspective on Drug Development Implications

Zamek‐Gliszczynski

Patel

Yang

et al. 2020

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

There is an increasing interest in transporter induction (i.e., decreased systemic drug exposure due to increased efflux‐limited absorption or transporter‐mediated clearance) as a mechanism of drug–drug interactions (DDIs), although evidence of clinical relevance is still evolving. Intestinal P‐glycoprotein (P‐gp) and hepatic organic anion transporting polypeptides 1B (OATP1B) can be important determinants of drug absorption and disposition, as well as targets for DDIs. Current data indicate that intestinal P‐gp protein levels can be induced up to threefold to fourfold in humans primarily with pregnane X receptor (PXR) activators, and that this induction can decrease the systemic exposure of drugs with P‐gp efflux‐limited absorption (e.g., ≤ 67% decrease in the exposure of total dabigatran following rifampin multiple oral dosing). Evaluation of the clinical relevance of P‐gp induction as a DDI mechanism must consider the induction potential of the perpetrator drug for P‐gp and attenuation of exposure of the victim drug in the context of its therapeutic window. Practical drug development recommendations are provided herein. Reports are contradictory on OATP1B induction by PXR activators in human hepatocytes and liver biopsies. Some clinical investigations demonstrated that rifampin pretreatment decreased exposure of OATP1B substrates, while other studies found no differences, and the potential involvement of other mechanisms in these observed DDIs cannot be definitively ruled out. Thus, further studies are needed to understand hepatic OATP1B induction and potential involvement of other mechanisms contributing to reduced exposure of OATP1B substrates. This review critically summarizes the state‐of‐the‐art on intestinal P‐gp and hepatic OATP1B induction, and highlights implications for drug development.

show abstract

“…Increased duodenal ABCB1 mRNA after multiple doses of rifampicin 600 mg dose were reported to be 1.55-fold to 3.67-fold 18,19 . Further, Yamazaki et al investigated rifampicin's P-gp induction effects with several P-gp substrates using PBPK modeling and simulation and demonstrated a 3-fold to 4-fold increase in intestinal P-gp activity reasonably predicted the DDI between rifampicin and P-gp substrates 20 . Taken together, the fold increase in intestinal P-gp after rifampicin 600 mg multiple dose was defined to be 3.5-fold.…”

Section: Accepted Articlementioning

confidence: 99%

Physiologically‐Based Pharmacokinetic Modeling for the Prediction of a Drug–Drug Interaction of Combined Effects on P‐glycoprotein and Cytochrome P450 3A

Otsuka

Choules

Bonate

et al. 2020

CPT Pharmacom & Syst Pharma

View full text Add to dashboard Cite

Direct oral anticoagulants, like apixaban and rivaroxaban, are important for the treatment and prophylaxis of venous thromboembolism and to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Since apixaban and rivaroxaban are predominantly eliminated by CYP3A and P-glycoprotein (P-gp), concomitant use of combined P-gp and strong CYP3A4 inhibitors and inducers should be avoided. Physiologically-based pharmacokinetic (PBPK) models for apixaban and rivaroxaban were developed to estimate the net effect of CYP3A induction, P-gp inhibition and P-gp induction by rifampicin. The disposition of rivaroxaban is more complex compared to apixaban since both hepatic and renal P-gp is considered to contribute to rivaroxaban elimination. Furthermore, organic anion transporter-3 (OAT3), a renal uptake transporter, may also contribute the elimination of rivaroxaban from systemic circulation. The models were verified with observed clinical drug-drug interactions with CYP3A and P-gp inhibitors. With the developed models, the predicted AUC and C max ratios were 0.43 and 0.48, respectively, for apixaban, and 0.50 to 0.52 and 0.72 to 0.73, respectively, for rivaroxaban when co-administered with 600 mg multiple dose of rifampicin and which were very close to observed data. The impact of each of the elimination pathways was assessed for rivaroxaban and inhibition of CYP3A led to a larger impact over intestinal and hepatic P-gp. Inhibition of renal OAT3 or P-gp led to an overall modest interaction. The developed apixaban and rivaroxaban models can be further applied to the investigation of interaction with other P-gp and/or CYP3A4 inhibitors and inducers.

show abstract

Physiologically‐Based Pharmacokinetic Modeling Approach to Predict Rifampin‐Mediated Intestinal P‐Glycoprotein Induction

Cited by 45 publications

References 47 publications

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

Effect of P-glycoprotein (P-gp) Inducers on Exposure of P-gp Substrates: Review of Clinical Drug–Drug Interaction Studies

Intestinal P‐gp and Putative Hepatic OATP1B Induction: International Transporter Consortium Perspective on Drug Development Implications

Physiologically‐Based Pharmacokinetic Modeling for the Prediction of a Drug–Drug Interaction of Combined Effects on P‐glycoprotein and Cytochrome P450 3A

Contact Info

Product

Resources

About