Weak Inhibitor Of CYP3A Research Articles

Pharmacokinetic study of capivasertib and the CYP3A4 substrate midazolam in patients with advanced solid tumors

PurposeCapivasertib, a potent, selective inhibitor of all three AKT serine/threonine kinase (AKT) isoforms, is being evaluated in phase 3 trials in advanced breast and prostate cancer. This study evaluated the drug–drug interaction risk of capivasertib with the cytochrome P450 3A substrate midazolam in previously treated adults with advanced solid tumors.MethodsPatients received oral capivasertib 400 mg twice daily (BID) on an intermittent schedule (4 days on/3 days off) starting on day 2 of cycle 1 (29 days) and on day 1 of each 28-day cycle thereafter. In cycle 1 only, patients received oral midazolam (1 mg) on day 1 (alone), and days 8 and 12 (3rd day off and 4th day on capivasertib, respectively). Midazolam pharmacokinetics on days 8 and 12 were analyzed versus day 1. Capivasertib, with or without standard-of-care treatment, was continued in patients deemed likely to benefit. Safety and exploratory efficacy analyses were conducted.ResultsCapivasertib–midazolam coadministration increased midazolam exposure (n = 21): geometric mean ratio (90% confidence interval) AUCinf and Cmax was 1.13 (0.97–1.32) and 1.15 (0.99–1.33) for day 8 versus day 1, and 1.75 (1.50–2.05) and 1.25 (1.08–1.46) for day 12 versus day 1. The capivasertib safety profile was manageable when administered with or without midazolam. Two patients had partial responses to treatment.ConclusionThe up to 1.75-fold increase in midazolam exposure indicates capivasertib is a weak CYP3A inhibitor at 400 mg BID on an intermittent schedule. Capivasertib was well tolerated; exploratory efficacy analysis demonstrated evidence of clinical activity in this heavily pre-treated population.ClinicalTrials.gov: NCT04958226.

Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug-Drug and Drug-Disease Interactions of Apatinib.

Aim: Apatinib is an orally administered vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitors approved for the treatment of advanced gastric adenocarcinoma or gastric esophageal junction adenocarcinoma. Apatinib is predominantly metabolized by CYP3A4/5, followed by CYP2D6. The present study aimed to evaluate the potential drug–drug interaction (DDI) and drug–disease interaction (DDZI) risks of apatinib in Chinese volunteers. Methods: Modeling and simulation were conducted using Simcyp Simulator. The input parameters required for modeling were obtained from literature research or experiments. Then, the developed physiologically based pharmacokinetic (PBPK) models were applied to evaluate single-dose DDI potential in Chinese healthy volunteers with weak and moderate CYP3A inhibitors, strong CYP2D6 inhibitors, as well as CYP3A4 inducers. The DDZI potential was also predicted in patients with hepatic or renal impairment. Results: The developed PBPK models accurately assessed apatinib pharmacokinetics following single-dose administration in Chinese healthy volunteers and cancer patients. The DDI simulation showed 2–4-fold changes in apatinib exposures by moderate CYP3A4 inhibitors and CYP3A4 inducers. A moderate increase of apatinib exposure (1.25–2-fold) was found with strong CYP2D6 inhibitor. In the DDZI simulation with hepatic impairment, the AUC of apatinib was significantly increased by 2.25-fold and 3.04-fold for Child–Pugh B and Child–Pugh C, respectively, with slightly decreased Cmax by 1.54 and 1.67-fold, respectively. Conclusion: The PBPK models developed in the present study would be highly beneficial to quantitatively predict the pharmacokinetic changes of apatinib under different circumstances, which might be difficult to evaluate clinically, so as to avoid some risks in advance.

Physiologically-based pharmacokinetic modeling to predict drug interactions of lemborexant with CYP3A inhibitors.

Lemborexant, a recently approved dual orexin receptor antagonist for treatment of adults with insomnia, is eliminated primarily by cytochrome P450 (CYP)3A metabolism. The recommended dose of lemborexant is 5 mg once per night, with a maximum recommended dose of 10 mg once daily. A physiologically‐based pharmacokinetic (PBPK) model for lemborexant was developed and applied to integrate data obtained from in vivo drug–drug interaction (DDI) assessments, and to further explore lemborexant interaction with CYP3A inhibitors and inducers. The model predictions were in good agreement with observed pharmacokinetic data and with DDI results from clinical studies with CYP3A inhibitors, itraconazole and fluconazole. The model further predicted that DDI effects of weak CYP3A inhibitors (fluoxetine and ranitidine) are weak, and effects of moderate inhibitors (erythromycin and verapamil) are moderate. Based on the PBPK simulations and clinical efficacy and safety data, the maximum daily recommended lemborexant dose when administered with weak CYP3A inhibitors is 5 mg; co‐administration of moderate and strong inhibitors should be avoided except in countries where 2.5 mg has been approved.

Physiologically Based Pharmacokinetic Modeling Suggests Limited Drug-Drug Interaction for Fesoterodine When Coadministered With Mirabegron.

5-Hydroxymethyl tolterodine (5-HMT; the active fesoterodine metabolite) is metabolized via the cytochrome P450 (CYP) 2D6 and CYP3A pathways. Mirabegron is a moderate CYP2D6 inhibitor and weak CYP3A inhibitor. Potential drug-drug interactions (DDIs) following coadministration of these 2 overactive bladder treatments were estimated using physiologically based pharmacokinetic models, developed and verified by comparing predicted and observed pharmacokinetic profiles from clinical studies. Models predicted and verified mirabegron and desipramine (CYP2D6 substrate) and 5-HMT and ketoconazole (strong CYP3A inhibitor) DDIs. Mirabegron model-predicted mean steady-state AUC and Cmax were within 11% of clinical observations. The predicted versus observed geometric mean ratio (GMR) of AUCinf for CYP2D6 substrates desipramine and metoprolol coadministered with mirabegron 100 or 160mg once daily were 3.47 versus 3.41 and 2.97 versus 3.29, respectively, indicating that the mirabegron model can be used to predict clinical CYP2D6 inhibition. 5-HMT fractional clearance by CYP3A and CYP2D6 was verified from clinical DDI studies with a potent CYP3A4 inhibitor (ketoconazole) and inducer (rifampicin) in CYP2D6 extensive and poor metabolizers and with a moderate CYP3A inhibitor (fluconazole) in healthy volunteers. 5-HMT AUCinf and Cmax GMRs for fesoterodine DDIs were all predicted within 1.26-fold of clinical observation, providing verification for the fesoterodine substrate model. The predicted changes in 5-HMT AUCinf and Cmax ratios for 8 mg fesoterodine when coadministered with 50 mg mirabegron were 1.22-fold and 1.17-fold, respectively, relative to 8 mg fesoterodine given alone. This modest increase in 5-HMT exposures by approximately 20% is considered clinically insignificant and would not require fesoterodine dose adjustment when coadministered with mirabegron within approved daily-dose ranges.

4β-Hydroxycholesterol as an Endogenous Biomarker for CYP3A Activity: Literature Review and Critical Evaluation.

A number of cytochrome P450 (CYP)3A phenotyping probes have been used to characterize the drug interaction potential of new molecular entities; of these, midazolam has emerged as the gold standard. Recently, plasma 4β-hydroxycholesterol (4β-OHC), the metabolite of CYP3A-mediated cholesterol metabolism, has been championed as an endogenous biomarker for CYP3A, particularly during chronic conditions where CYP3A activity is altered by disease and in long-term treatment studies where midazolam administration is not optimal. Multiple studies in humans have shown that 4β-OHC can qualitatively differentiate among weak, moderate, and potent CYP3A induction when an inducer, typically rifampin, is administered for up to 2weeks. Conversely, longer durations of CYP3A inhibitor administration (≥1month) appear to be necessary to differentiate among weak, moderate, and potent CYP3A inhibitors. A number of studies have reported statistically significant linear relationships between 4β-OHC plasma concentrations (and 4β-OHC:cholesterol ratios) and midazolam clearance. However, sufficiently powered studies assessing the ability of 4β-OHC or 4β-OHC:cholesterol ratios to measure CYP3A activity (ie, predictive performance) have not been conducted to date. Additional limitations associated with 4β-OHC phenotyping include inability to detect acute changes in CYP3A activity, uncertainty with regard to its intestinal formation, ambiguity surrounding the role of CYP3A5 in its metabolism, and lack of clarity regarding the role of transporters in its disposition. As such, the data do not support the use of 4β-OHC or 4β-OHC:cholesterol ratios as an endogenous biomarker for CYP3A activity.

Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations.

We report physiologically based pharmacokinetic‐modeling analyses to determine olaparib (tablet or capsule) drug–drug interactions (DDIs). Verified DDI simulations provided dose recommendations for olaparib coadministration with clinically relevant CYP3A4 modulators to eliminate potential risk to patient safety or olaparib efficacy. When olaparib is given with strong/moderate CYP3A inhibitors, the dose should be reduced to 100/150 mg b.i.d. (tablet), and 150/200 mg b.i.d. (capsule). Olaparib administration is not recommended with strong/moderate CYP3A inducers. No dose reductions are required with weak CYP3A inhibitors/inducers. Olaparib was shown to be a weak inhibitor of CYP3A (1.6‐fold increase in exposure of a sensitive CYP3A probe) and to have no effect on P‐glycoprotein or UGT1A1 substrates. Finally, this model was used to simulate exposure in scenarios where clinical data of olaparib are lacking, such as severe renal or hepatic impairment populations, and provided initial dosing recommendations in pediatric patients.

Application of Physiologically Based Pharmacokinetic Modeling to the Understanding of Bosutinib Pharmacokinetics: Prediction of Drug-Drug and Drug-Disease Interactions.

Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Bosutinib is predominantly metabolized by CYP3A4 as the primary clearance mechanism. The main objectives of this study were to 1) develop physiologically based pharmacokinetic (PBPK) models of bosutinib; 2) verify and refine the PBPK models based on clinical study results of bosutinib single-dose drug-drug interaction (DDI) with ketoconazole and rifampin, as well as single-dose drug-disease interaction (DDZI) in patients with renal and hepatic impairment; 3) apply the PBPK models to predict DDI outcomes in patients with weak and moderate CYP3A inhibitors; and 4) apply the PBPK models to predict DDZI outcomes in renally and hepatically impaired patients after multiple-dose administration. Results showed that the PBPK models adequately predicted bosutinib oral exposures in patients after single- and multiple-dose administrations. The PBPK models also reasonably predicted changes in bosutinib exposures in the single-dose DDI and DDZI results, suggesting that the PBPK models were sufficiently developed and verified based on the currently available data. Finally, the PBPK models predicted 2- to 4-fold increases in bosutinib exposures by moderate CYP3A inhibitors, as well as comparable increases in bosutinib exposures in renally and hepatically impaired patients between single- and multiple-dose administrations. Given the challenges in conducting numerous DDI and DDZI studies of anticancer drugs in patients, we believe that the PBPK models verified in our study would be valuable to reasonably predict bosutinib exposures under various scenarios that have not been tested clinically.

Pharmacokinetics of Venetoclax, a Novel BCL-2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin Lymphoma.

Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.

Physiologically Based Pharmacokinetic Modeling of Palbociclib

Palbociclib is an orally available CDK4/6 inhibitor. In humans, palbociclib undergoes metabolism mediated primarily by CYP3A and SULT2A1, and it is also a weak time-dependent CYP3A inhibitor. The objectives of the current study are to (1) develop a physiologically based pharmacokinetic (PBPK) model of palbociclib based on the in silico, in vitro, and in vivo pharmacokinetic data of palbociclib, (2) verify the PBPK model with clinical drug-drug interaction (DDI) results of palbociclib with strong CYP3A inhibitor (itraconazole), inducer (rifampin), and a sensitive CYP3A substrate (midazolam), and (3) predict the DDI risk of palbociclib with moderate/weak CYP3A inhibitors. The developed PBPK model adequately described the observed pharmacokinetics of palbociclib after administration of a single oral or intravenous dose of palbociclib. The model-predicted DDIs of palbociclib with itraconazole, rifampin, and midazolam were consistent with the observed DDIs, with the discrepancies of the predicted vs observed AUCR and Cmax R within 20%, except for the AUC ratio of palbociclib with coadministration of rifampin. Using this final PBPK model, it was predicted that weak CYP3A inhibitors (fluoxetine and fluvoxamine) are anticipated to have negligible DDI risk with palbociclib, whereas moderate CYP3A inhibitors (diltiazem and verapamil) may increase plasma palbociclib AUC by ∼40%. A moderate CYP3A inducer (efavirenz) may decrease plasma palbociclib AUC by ∼40%. The established model is considered sufficiently robust for other applications in support of the continued development for palbociclib.

Evaluation of Cytochrome P450 3A4-Mediated Drug-Drug Interaction Potential for Cobimetinib Using Physiologically Based Pharmacokinetic Modeling and Simulation.

Cobimetinib is eliminated mainly through cytochrome P450 (CYP) 3A4-mediated hepatic metabolism in humans. A clinical drug-drug interaction (DDI) study with the potent CYP3A4 inhibitor itraconazole resulted in an approximately sevenfold increase in cobimetinib exposure. The DDI risk for cobimetinib with other CYP3A4 inhibitors and inducers needs to be assessed in order to provide dosing instructions. A physiologically based pharmacokinetic (PBPK) model was developed for cobimetinib using in vitro data. It was then optimized and verified using clinical pharmacokinetic data and itraconazole-cobimetinib DDI data. The contribution of CYP3A4 to the clearance of cobimetinib in humans was confirmed using sensitivity analysis in a retrospective simulation of itraconazole-cobimetinib DDI data. The verified PBPK model was then used to predict the effect of other CYP3A4 inhibitors and inducers on cobimetinib pharmacokinetics. The PBPK model described cobimetinib pharmacokinetic profiles after both intravenous and oral administration of cobimetinib well and accurately simulated the itraconazole-cobimetinib DDI. Sensitivity analysis suggested that CYP3A4 contributes ~78% of the total clearance of cobimetinib. The PBPK model predicted no change in cobimetinib exposure (area under the plasma concentration-time curve, AUC) with the weak CYP3A inhibitor fluvoxamine and a three to fourfold increase with the moderate CYP3A inhibitors, erythromycin and diltiazem. Similarly, cobimetinib exposure in the presence of strong (rifampicin) and moderate (efavirenz) CYP3A inducers was predicted to decrease by 83 and 72%, respectively. This study demonstrates the value of using PBPK simulation to assess the clinical DDI risk inorder to provide dosing instructions with other CYP3A4 perpetrators.

Simulation and Prediction of the Drug‐Drug Interaction Potential of Naloxegol by Physiologically Based Pharmacokinetic Modeling

Naloxegol, a peripherally acting μ‐opioid receptor antagonist for the treatment of opioid‐induced constipation, is a substrate for cytochrome P450 (CYP) 3A4/3A5 and the P‐glycoprotein (P‐gp) transporter. By integrating in silico, preclinical, and clinical pharmacokinetic (PK) findings, minimal and full physiologically based pharmacokinetic (PBPK) models were developed to predict the drug‐drug interaction (DDI) potential for naloxegol. The models reasonably predicted the observed changes in naloxegol exposure with ketoconazole (increase of 13.1‐fold predicted vs. 12.9‐fold observed), diltiazem (increase of 2.8‐fold predicted vs. 3.4‐fold observed), rifampin (reduction of 76% predicted vs. 89% observed), and quinidine (increase of 1.2‐fold predicted vs. 1.4‐fold observed). The moderate CYP3A4 inducer efavirenz was predicted to reduce naloxegol exposure by ∼50%, whereas weak CYP3A inhibitors were predicted to minimally affect exposure. In summary, the PBPK models reasonably estimated interactions with various CYP3A modulators and can be used to guide dosing in clinical practice when naloxegol is coadministered with such agents.

Pharmacokinetic interaction of intravenous fentanyl with ketoconazole.

Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open-label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0- ∞ ) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N-dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity.

Abstract CT419: A phase 1 randomized, open-label, 2-sequence, 2-period crossover study of the effect of multiple doses of palbociclib (PD-0332991) on midazolam pharmacokinetics in healthy women of non-childbearing potential

Abstract Introduction: Palbociclib (PD‑0332991) is an oral cyclin‑dependent kinase (CDK) 4/6 inhibitor currently in Phase 2 and Phase 3 clinical trials in multiple oncology indications. In vitro, palbociclib and its active lactam metabolite (PF‑05089326) caused time‑dependent inhibition of CYP3A-mediated midazolam 1’‑hydroxylase and testosterone 6β‑hydroxylase activities. The primary objective of this study is to investigate the effect of multiple doses of palbociclib on the pharmacokinetics of a single oral dose of the sensitive CYP3A4/5 probe substrate midazolam in healthy women of non-childbearing potential. Methods: This was an open label, randomized, 2‑period 2‑sequence study of the effect of multiple oral doses of palbociclib on midazolam pharmacokinetics in 26 healthy female volunteers of non-childbearing potential. Simulations were performed with SimCYP, using the in vitro CYP inhibition data and human pharmacokinetic data for palbociclib from Study A5481001 as inputs, to optimize the duration of dosing and washout periods. Each subject received two treatments (Treatment A = 2 mg oral dose of midazolam alone, Treatment B = 2 mg oral dose of midazolam on Day 7 of an 8-day 125 mg QD palbociclib dose regimen) in a crossover scheme. Subjects were randomized to one of two sequences (Sequence 1 = A→B, Sequence 2 = B→A). In Sequence 2 there was a washout period of no less than 14 days after the last administered dose of palbociclib to ensure that there was no carryover effect of CYP3A inhibition into Period 2. Serial blood sampling for midazolam pharmacokinetics was performed up to 36 hours post-midazolam dose in both periods. Palbociclib pre-dose blood sampling was performed on specified visits to document achievement of steady-state concentrations. Plasma concentrations of midazolam and palbociclib were each measured using validated LC/MS/MS (liquid chromatography- tandem mass spectrometry) methods. Midazolam plasma pharmacokinetic (PK) parameters were estimated using standard non-compartmental methods. Discussion:In general, palbociclib reached steady-state levels prior to co-administration of midazolam, allowing for a worst case assessment of the potential palbociclib-mediated time-dependent CYP3A inhibition. Midazolam geometric mean Cmax and AUCinf values increased 37% and 61%, respectively, when midazolam was co-administered with multiple doses of palbociclib as compared to its administration alone. These results indicate that palbociclib is a weak CYP3A inhibitor following daily 125 mg dosing at steady-state according to the FDA classification. In general, the combination of palbociclib and midazolam were well tolerated with no reported serious adverse events or treatment discontinuations. Reversible neutropenia was reported in 15 out of the 26 subjects. Citation Format: Justin T. Hoffman, Anna Plotka, Melissa O'Gorman, Cho-Ming Loi, Leonid Kirkovsky, Corrado Gallo-Stampino, Diane Wang. A phase 1 randomized, open-label, 2-sequence, 2-period crossover study of the effect of multiple doses of palbociclib (PD-0332991) on midazolam pharmacokinetics in healthy women of non-childbearing potential. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT419. doi:10.1158/1538-7445.AM2014-CT419

Clinical drug‐drug interaction assessment of ivacaftor as a potential inhibitor of cytochrome P450 and P‐glycoprotein

Ivacaftor is approved in the USA for the treatment of cystic fibrosis (CF) in patients with a G551D-CFTR mutation or one of eight other CFTR mutations. A series of in vitro experiments conducted early in the development of ivacaftor indicated ivacaftor and metabolites may have the potential to inhibit cytochrome P450 (CYP) 2C8, CYP2C9, CYP3A, and CYP2D6, as well as P-glycoprotein (P-gp). Based on these results, a series of clinical drug-drug interaction (DDI) studies were conducted to evaluate the effect of ivacaftor on sensitive substrates of CYP2C8 (rosiglitazone), CYP3A (midazolam), CYP2D6 (desipramine), and P-gp (digoxin). In addition, a DDI study was conducted to evaluate the effect of ivacaftor on a combined oral contraceptive, as this is considered an important comedication in CF patients. The results indicate ivacaftor is a weak inhibitor of CYP3A and P-gp, but has no effect on CYP2C8 or CYP2D6. Ivacaftor caused non-clinically significant increases in ethinyl estradiol and norethisterone exposure. Based on these results, caution and appropriate monitoring are recommended when concomitant substrates of CYP2C9, CYP3A and/or P-gp are used during treatment with ivacaftor, particularly drugs with a narrow therapeutic index, such as warfarin.

Role of CYP3A in regulating hepatic clearance and hepatotoxicity of triptolide in rat liver microsomes and sandwich-cultured hepatocytes

Triptolide (TP) is an active component of Tripterygium wilfordii Hook. F and widely used to treat autoimmune and inflammatory diseases. It has been demonstrated that cytochrome P450 (CYP) are involved in the metabolism of TP. However, the underlying mechanisms of TP-induced toxicity mediated by hepatic CYP have not been well delineated. In this study, rat liver microsomes (RLM) and sandwich-cultured rat hepatocytes (SCRH) were used to identify the mechanism involving the CYP3A inhibition by TP and to evaluate TP-induced liver damage after CYP3A modulation by the known inhibitor, ketoconazole, and the known inducer, dexamethasone. The results showed that TP itself had a time- and concentration-dependent inhibitory effect on CYP3A. When the CYP3A inhibitor and inducer were added, the enzyme activity and hepatotoxicity changed significantly. The enzyme inducer increased CYP3A activity and decreased the metabolic half life (t1/2) of TP when compared to the control group, while the enzyme inhibitor had an opposite effect. Our findings reveal that TP is a weak CYP3A inhibitor involving the time-dependent inhibition mechanism. The induction or inhibition of CYP3A played an important role in TP-induced hepatotoxicity. Clinicians should be aware of the metabolic characteristics of TP to maximize therapeutic efficacy and reduce TP-induced toxicity.

In Vitro Analysis and Quantitative Prediction of Efavirenz Inhibition of Eight Cytochrome P450 (CYP) Enzymes: Major Effects on CYPs 2B6, 2C8, 2C9 and 2C19

In order to quantitatively predict drug interactions associated with efavirenz-based anti-HIV therapy, we evaluated reversible and time-dependent inhibitions of efavirenz on eight cytochrome P450 (CYP) enzymes in vitro. The present study showed that efavirenz was a potent competitive inhibitor of CYP2B6 (average K(i) = 1.68 µM in HLMs and K(i) = 1.38 µM in expressed CYP2B6) and CYP2C8 (K(i) = 4.78 µM in pooled HLMs and K(i) = 4.80 µM in HLMs with CYP2C8*3/*3 genotype). Efavirenz was a moderate inhibitor of CYP2C9 (K(i) = 19.46 µM) and CYP2C19 (K(i) = 21.31 µM); and a weak inhibitor of CYP3A (K(i) = 40.33 µM). No appreciable inhibition was observed on CYP1A2, CYP2A6 or CYP2D6. No time-dependent inhibition of the CYPs by efavirenz was observed in this study. Quantitative predictions showed that single dose of efavirenz may substantially slow the elimination of drugs predominantly cleared by CYP2B6, CYP2C19 or by both enzymes and may also lower the area under the plasma concentration time curve (AUC) of active metabolites of some pro-drugs (e.g., clopidogrel and proguanil) by up to 30%. Depending on substrates, chronic administration of efavirenz may increase the AUC of CYP2C8 and CYP2C9 substrates about 3.5-4.4-fold and 1.7-2.0-fold at steady state.

No Dose Adjustment on Coadministration of the PDE4 Inhibitor Roflumilast With a Weak CYP3A, CYP1A2, and CYP2C19 Inhibitor: An Investigation Using Cimetidine

This nonrandomized, fixed-sequence, 2-period crossover study investigated potential pharmacokinetic interactions between the phosphodiesterase 4 inhibitor roflumilast, currently in clinical development for the treatment of chronic obstructive pulmonary disease, and the histamine 2 agonist cimetidine. Participants received roflumilast, 500 µg once daily, on days 1 and 13. Cimetidine, 400 mg twice daily, was administered from days 6 to 16. Pharmacokinetic analysis of roflumilast and its active metabolite roflumilast N-oxide was performed, and the ratio of geometric means for roflumilast alone and concomitantly with steady-state cimetidine was calculated. The effect of cimetidine on the total PDE4 inhibitory activity (tPDE4i; total exposure to roflumilast and roflumilast N-oxide) was also calculated. Coadministration of steady-state cimetidine increased mean tPDE4i of roflumilast and roflumilast N-oxide by about 47%. The maximum plasma concentration (C(max)) of roflumilast increased by about 46%, with no effect on C(max) of roflumilast N-oxide. The increase in tPDE4i of roflumilast and roflumilast N-oxide following coadministration with cimetidine was mainly due to the inhibitory effect of cimetidine on cytochrome P450 (CYP) isoenzymes CYP1A2, CYP3A, and CYP2C19. These moderate changes indicate that dose adjustment of roflumilast is not required when coadministered with a weak inhibitor of CYP1A2, CYP3A, and CYP2C19, such as cimetidine.

Ranolazine-Tacrolimus Interaction

To report the case of a kidney allograft recipient on a stable regimen of tacrolimus who exhibited increased tacrolimus concentrations within 24 hours of initiating ranolazine. A 64-year-old kidney allograft recipient on a stable dose of tacrolimus (10 mg twice daily) was admitted for recent worsening of her chronic anginal pain. The patient was initiated on ranolazine 500 mg twice daily on hospital day 2. Tacrolimus concentrations rose from 7.0-10.1 ng/mL preadmission to 17.8 ng/mL within 24 hours of ranolazine initiation. Ranolazine therapy was continued due to the patient's beneficial response; therefore, the tacrolimus dose was eventually decreased by 70% to 3 mg twice daily to maintain steady-state trough concentrations between 6.6 and 7.9 ng/mL with ranolazine therapy. Ranolazine dechallenge on a subsequent admission produced subtherapeutic tacrolimus concentrations requiring dosage increases. Ranolazine, an antianginal agent, is both a substrate and a weak inhibitor of CYP3A as well as a substrate and moderate inhibitor of the P-glycoprotein (P-GP) efflux transport system. Tacrolimus, an immunosuppressant, is also a substrate of CYP3A and P-GP. Through possible inhibition of both P-GP- and CYP3A-mediated first-pass metabolism and CYP3A systemic metabolism, ranolazine may have significantly increased serum concentrations of tacrolimus necessitating an eventual 70% decrease in the tacrolimus dose. Based on the Horn Drug Interaction Probability Scale, this interaction is possible. We suggest that the eventual 70% decrease in tacrolimus dose after ranolazine initiation may indicate that ranolazine decreases the metabolism and clearance of tacrolimus, causing an elevation in tacrolimus concentrations and the potential for tacrolimus toxicity. Clinicians should be aware of this possible interaction when initiating ranolazine in patients on tacrolimus.

Everolimus drug interactions: application of a classification system for clinical decision making

More than half of all drugs used in medical practice are metabolized by cytochrome CYP3A. Coadministration of drugs that share this elimination pathway may lead to pharmacokinetic drug interactions. Efforts are underway by clinical, drug development and regulatory scientists to classify CYP3A-related drug interactions with the ultimate goal of improving guidance for clinical intervention. The CYP3A inhibitory classification system ranks inhibitors according to the fold-increase in area-under-the-curve (AUC) of a probe substrate as: strong (> or =5-fold), moderate (>2.0- to 4.9-fold), or weak (< or =2.0-fold). This classification system was applied to characterize everolimus as a CYP3A substrate.Methods. Five open-label crossover drug interaction studies were performed in 12-16 healthy subjects each. Subjects received a single 2 mg dose of everolimus alone and again during single- or multiple-dose treatment with the probe inhibitors ketoconazole, erythromycin, verapamil, cyclosporine and atorvastatin.Results. The fold-increase in everolimus AUC was: 15.0 with the strong inhibitor ketoconazole; 4.4, 3.5 and 2.7 with the moderate inhibitors erythromycin, verapamil and cyclosporine; and no change with the weak inhibitor atorvastatin. Subjects with low baseline AUCs when everolimus was given alone tended to have AUC increases of a higher magnitude (more potent interaction) in the presence of an inhibitor.Conclusions. Strong CYP3A inhibitors should be avoided when possible during everolimus treatment as compensatory everolimus dose reductions could be difficult to manage. Everolimus therapeutic drug monitoring should be used to guide individualized dose adjustments when moderate CYP3A inhibitors are added to or withdrawn from the regimen. Routine everolimus therapeutic drug monitoring should be sufficient to determine whether dose adjustments are needed when weak CYP3A inhibitors are coadministered. This rational and systematic approach to drug interactions on everolimus yielded clinically useful, structured guidelines for dose adjustment.

Clinical Pharmacokinetics of Ranolazine

Ranolazine is a compound that is approved by the US FDA for the treatment of chronic angina pectoris in combination with amlodipine, beta-adrenoceptor antagonists or nitrates, in patients who have not achieved an adequate response with other anti-anginals. The anti-anginal effect of ranolazine does not depend on changes in heart rate or blood pressure. It acts through different pharmacological mechanisms where inhibition of the late inward sodium current (reducing calcium overload and thereby left ventricular diastolic tension) is one plausible mechanism of reduced oxygen consumption. Initial studies used an oral solution or an immediate-release (IR) capsule, but subsequently an extended-release (ER) formulation was developed to allow for twice-daily administration with maintained efficacy. Following administration of an oral solution or IR capsule, peak plasma concentrations (C(max)) are observed within 1 hour. After administration of radiolabelled ranolazine, 73% of the dose was excreted in urine, and unchanged ranolazine accounted for <5% of radioactivity in both urine and faeces. The absolute bioavailability ranges from 35% to 50%. Food has no effect on rate or extent of absorption from the ER formulation. Ranolazine protein binding is about 61-64% over the therapeutic concentration range. Volume of distribution at steady state ranges from 85 to 180 L. Ranolazine is extensively metabolised by cytochrome P450 (CYP) 3A enzymes and, to a lesser extent, by CYP2D6, with approximately 5% excreted renally unchanged. Elimination half-life of ranolazine is 1.4-1.9 hours but is apparently prolonged, on average, to 7 hours for the ER formulation as a result of extended absorption (flip-flop kinetics). Elimination occurs through parallel linear and saturable elimination pathways, where the saturable pathway is related to CYP2D6, which is partly inhibited by ranolazine. Oral plasma clearance diminishes with dose from, on average, 45 L/h at 500 mg twice daily to 33 L/h at 1000 mg twice daily. The departure from dose proportionality for this dose range is modest, with increases in steady-state C(max) and area under plasma concentration-time curve (AUC) from 0 to 12 hours of 2.5- and 2.7-fold, respectively. Ranolazine pharmacokinetics are unaffected by sex, congestive heart failure and diabetes mellitus. AUC increases up to 2-fold with advancing degree of renal impairment. Ranolazine is a weak inhibitor of CYP3A, and increases AUC and C(max) for simvastatin, its metabolites and HMG-CoA reductase inhibitor activity <2-fold. Digoxin AUC is increased 40-60% by ranolazine through P-glycoprotein inhibition. Ranolazine AUC is increased by CYP3A inhibitors ranging from 1.5-fold for diltiazem 180 mg once daily to 3.9-fold for ketoconazole 200 mg twice daily. Verapamil increases ranolazine exposure approximately 2-fold. CYP2D6 inhibition has a negligible effect on ranolazine exposure.