Verification of a physiologically based pharmacokinetic model of ritonavir to estimate drug–drug interaction potential of CYP3A4 substrates

Umehara, Kenichi; Huth, Felix; Won, Christina S.; Heimbach, Tycho; He, Handan

doi:10.1002/bdd.2122

Cited by 14 publications

(19 citation statements)

References 29 publications

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“…Based on ultrasound imaging, Ramsay et al [25] reported the presence of an average nine milk ducts (range [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] in the human breast, confirming reports of other investigators. The same study revealed milk duct diameters ranging between 1 and 4.4 mm.…”

Section: Anatomy Physiology and Cell Biology Of The Mammary Gland In Relation To Drug Milk Excretionmentioning

confidence: 57%

“…Nevertheless, combining nonclinical data with PBPK modelling and simulation [6], is emerging as a powerful strategy to make reliable and quantitative predictions of in vivo drug behavior. Such a strategy has for instance been applied repeatedly for quantitative prediction of numerous drug-drug interactions ( [7][8][9][10][11][12][13][14][15][16]) or drug disposition in specific populations (e.g. pediatrics) [17][18][19][20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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Non-clinical Models to Determine Drug Passage into Human Breast Milk

Ventrella

Forni

Bacci

et al. 2019

CPD

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Background: Successful practice of clinical perinatal pharmacology requires a thorough understanding of the pronounced physiological changes during lactation and how these changes affect various drug disposition processes. In addition, pharmacokinetic processes unique to lactation have remained understudied. Hence, determination of drug disposition mechanisms in lactating women and their babies remains a domain with important knowledge gaps. Indeed, lack of data regarding infant risk during breastfeeding far too often results in discontinuation of breastfeeding and subsequent loss of all the associated benefits to the breastfed infant. In the absence of age-specific toxicity data, human lactation data alone are considered insufficient to rapidly generate the required evidence regarding risks associated with medication use during lactation. Methods: Systematic review of literature to summarize state-of-the art non-clinical approaches that have been developed to explore the mechanisms underlying drug milk excretion. Results: Several studies have reported methods to predict (to some extent) milk drug excretion rates based on physicochemical properties of the compounds. In vitro studies with primary mammary epithelial cells appear excellent approaches to determine transepithelial drug transport rates across the mammary epithelium. Several of these in vitro tools have been characterized in terms of transporter expression and activity as compared to the mammary gland tissue. In addition, with the advent of physiology-based pharmacokinetic (PBPK) modelling, these in vitro transport data may prove instrumental in predicting drug milk concentration time profiles prior to the availability of data from clinical lactation studies. In vivo studies in lactating animals have proven their utility in elucidating the mechanisms underlying drug milk excretion. Conclusion: By combining various non-clinical tools (physicochemistry-based, in vitro and PBPK, in vivo animal) for drug milk excretion, valuable and unique information regarding drug milk concentrations during lactation can be obtained. The recently approved IMI project ConcePTION will address several of the challenges outlined in this review.

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Section: Anatomy Physiology and Cell Biology Of The Mammary Gland In Relation To Drug Milk Excretionmentioning

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Non-clinical Models to Determine Drug Passage into Human Breast Milk

Ventrella

Forni

Bacci

et al. 2019

CPD

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“…Since RTV is the only clinical inhibitor and inducer of CYP3A4 within the regimen, only RTV was simulated as a surrogate for the RTV-containing regimens [35]. In addition, the PBPK model of RTV has been already verified by simulating its inhibition effects on the PK profiles of CYP3A4 substrates [36]. Thus, the RTV model was not herein verified.…”

Section: Nifedipine-rtv Ddi Predictionmentioning

confidence: 99%

Investigation on the interaction between nifedipine and ritonavir containing antivirus regimens: a physiologically-based pharmacokinetic/pharmacodynamic analysis

Niu

Jin

et al. 2020

Preprint

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Background and Objective Hypertension is a common comorbidity of patients with COVID-19, SARS or HIV infection. Those patients are often treated with commonly used antiviral and antihypertensive agents concomitantly, such as ritonavir-containing regimens and nifedipine. Since ritonavir is a strong inhibitor of CYP3A, when nifedipine is combined with ritonavir-containing antiviral drugs, there is a potential risk of drug-drug interaction. This study aimed to provide guidance on nifedipine treatment during and after co-administration with ritonavir-containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) analysis. Methods A PBPK/PD model was developed for nifedipine by the software of Simcyp, and the model was verified using published data. The effects of ritonavir on nifedipine exposures and systolic blood pressure were assessed for instant-release, sustained-release and controlled-release formulations. Moreover, various nifedipine regimens were investigated when co-administrated with and withdrawing ritonavir. Results PBPK/PD models for three formulations of nifedipine were successfully established. The model predicted pharmacokinetic profiles of nifedipine were comparable to the published data. Ratios of predicted versus observed AUCDDI/AUCNifedipine of nifedipine were within 0.70- to 1.83-fold. Model simulations showed that the inhibitory effect of ritonavir on CYP3A4 increased the Cmax of nifedipine by 9.82-34.35 times and the AUC by 44.94-50.77 times at steady state. Moreover, nifedipine dose reduced to 1/16 of the regular dose during ritonavir co-administration could lead to severe hypotension. Conclusions Ritonavir had a pronounced influence on the pharmacokinetics and antihypertensive effect of nifedipine. It is not recommended for patients to take nifedipine and ritonavir-containing regimens simultaneously.

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“…RTV, an antiretroviral drug, is a strong inhibitor of intestinal and hepatic CYP3A4/5 and gut P‐glycoprotein (P‐gp), and is used to evaluate the maximal CYP3A inhibition potential of substrates in clinical DDI studies. 13 , 14 Grapefruit juice is a strong inhibitor of intestinal but not hepatic CYP3A4/5, allowing differentiation when compared to the RTV results. 15 , 16 Remibrutinib was given orally; an intravenous microtracer was administered 2 h post‐remibrutinib in the form of a stable isotope labeled remibrutinib (SIL‐remibrutinib).…”

Section: Introductionmentioning

confidence: 99%

Novel Bruton’s Tyrosine Kinase inhibitor remibrutinib: Drug‐drug interaction potential as a victim of CYP3A4 inhibitors based on clinical data and PBPK modeling

Huth

Schiller

Jin

et al. 2021

Clinical Translational Sci

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Remibrutinib, a novel oral Bruton's Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib.The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first-pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady-state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27-fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically-based pharmacokinetic (PBPK) model, which well-described the therapeutic dose range of 25-100 mg. Simulations of untested scenarios revealed an absence of drug-drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration-time curve ratio[AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%.Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Remibrutinib is an irreversible Bruton's Tyrosine Kinase inhibitor and moderate CYP3A4 substrate to be administered with caution with strong inhibitors.

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Verification of a physiologically based pharmacokinetic model of ritonavir to estimate drug–drug interaction potential of CYP3A4 substrates

Cited by 14 publications

References 29 publications

Non-clinical Models to Determine Drug Passage into Human Breast Milk

Non-clinical Models to Determine Drug Passage into Human Breast Milk

Investigation on the interaction between nifedipine and ritonavir containing antivirus regimens: a physiologically-based pharmacokinetic/pharmacodynamic analysis

Novel Bruton’s Tyrosine Kinase inhibitor remibrutinib: Drug‐drug interaction potential as a victim of CYP3A4 inhibitors based on clinical data and PBPK modeling

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