Moderate CYP3A4 Inhibitor Research Articles

PBPK Modeling Strategy for Predicting Complex Drug Interactions of Letermovir as a Perpetrator in Support of Product Labeling.

Letermovir is a human cytomegalovirus (CMV) terminase inhibitor for the prophylaxis of CMV infection in allogeneic hematopoietic stem-cell transplant (HSCT) recipients. In vitro, letermovir is a time-dependent inhibitor and an inducer of cytochrome P450 (CYP)3A, and an inhibitor of CYP2C8 and organic anion transporting polypeptide (OATP)1B. A stepwise approach was taken to qualify the interaction model of an existing letermovir physiologically based pharmacokinetic model to predict letermovir interactions with CYP3A and OATP1B. The model was then used to prospectively predict the interaction between letermovir and CYP2C8 substrates such as repaglinide, a substrate of CYP2C8, CYP3A, and OATP1B. The results showed that letermovir modestly increased the exposure of CYP2C8 substrates. These results were used to inform the US prescribing information in the absence of clinical drug-drug interaction studies. In addition, midazolam interactions with letermovir at therapeutic doses were also simulated to confirm that letermovir is a moderate CYP3A inhibitor.

Effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in different CYP2D6 genotypes.

Tamsulosin, a selective antagonist of the α1-adrenoceptor, is primarily metabolized by CYP3A4 and CYP2D6, and tamsulosin exposure is significantly increased according to the genetic polymorphism of CYP2D6. In this study, we investigated the effects of diltiazem, a moderate inhibitor of CYP3A4, on the pharmacokinetics of tamsulosin in subjects with different CYP2D6 genotypes. Twenty-three healthy Korean male subjects with CYP2D6*wt/*wt (*wt = *1 or *2) and CYP2D6*10/*10 were enrolled in the prospective, open-label, two-phase parallel pharmacokinetic study. On the first day of study (day 1), each subject received a single 0.2mg oral dose of tamsulosin. After a washout period of 1week, on day 8, the subjects were given a 60mg oral dose of diltiazem three times daily for four days. On day 10, 1h after the morning dose of diltiazem, they received a single 0.2mg oral dose of tamsulosin. The pharmacokinetic parameters of tamsulosin in those with and without diltiazem treatment were compared in subjects with different CYP2D6 genotypes. After diltiazem treatment, the Cmax and AUCinf of tamsulosin in each CYP2D6 genotype group were significantly increased (p < 0.0001 for all). The CL/F of tamsulosin was also significantly decreased after diltiazem treatment (both p < 0.0001). However, diltiazem did not affect the t1/2 of tamsulosin in each genotype group. In conclusion, diltiazem significantly increases exposure to tamsulosin regardless of the genotype of CYP2D6. Dose adjustment in the daily maintenance dose of tamsulosin may improve tolerability and safety in patients receiving diltiazem.

Influence of aprepitant and localization of the patch on fentanyl exposure in patients with cancer using transdermal fentanyl.

Background and ObjectivesThe cutaneous fentanyl patch is widely used to treat continuous pain in patients with cancer. Its use is hampered by a high inter- and intrapatient pharmacokinetic variability. Factors that influence this pharmacokinetic variability are largely unclear. The aim of these studies was to test if common patient variables, i) the use of the moderate CYP3A4 inhibitor aprepitant and ii) the localization of the fentanyl patch (upper arm versus thorax) influence systemic exposure to fentanyl in patients with cancer using a transdermal fentanyl patch.ResultsThe AUC0–6 h of fentanyl was 7.1% (95% CI: −28% to +19%) lower if patients concurrently used aprepitant, compared to the period when patients used fentanyl only. The AUC0–4 h of fentanyl was 7.4% (95% CI: −22% to +49%) higher when the cutaneous fentanyl patch was applied to the upper arm compared to application at the thorax.ConclusionsNeither the concurrent use of aprepitant, nor the localization of the fentanyl patch showed a statistically significant influence on fentanyl pharmacokinetics.MethodsWe performed two prospective cross-over pharmacokinetic intervention studies. Both studies had two eight-day study periods. At day 8 of each study period blood samples were collected for pharmacokinetic analysis. In each study 14 evaluable patients were included.

Correction to: Development of Guanfacine Extended-Release Dosing Strategies in Children and Adolescents with ADHD Using a Physiologically Based Pharmacokinetic Model to Predict Drug-Drug Interactions with Moderate CYP3A4 Inhibitors or Inducers.

The article "Development of Guanfacine Extended-Release Dosing Strategies in Children and Adolescents with ADHD Using a PhysiologicallyBased Pharmacokinetic Model to Predict Drug-Drug Interactions with Moderate CYP3A4 Inhibitors or Inducers", written by Aiqun Li, Karen Yeo, Devin Welty, Haojing Rong, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 02nd November, 2017 without open access.

Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with Acute Myeloid Leukemia Unfit for Intensive Chemotherapy: 1-Year Outcomes

Background: Older patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy are unlikely to achieve remission with available therapy and have unacceptably short survival. Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC). Presented are long-term outcomes, including 1-year overall survival (OS) and biomarker analyses. Methods: This phase 1b/2, open-label study (NCT02287233) evaluates the safety and preliminary efficacy of orally administered VEN combined with LDAC in patients ≥65 years with previously untreated AML (except for hydroxyurea). Patients were ineligible for intensive chemotherapy because of comorbidity or other factors and had an ECOG performance score of 0-2, with adequate hepatic and renal function. Exclusion criteria were acute promyelocytic leukemia, active CNS involvement with AML, concominant use of moderate or strong CYP3A inhibitors, or prior treament with cytarabine for a preexisting myeloid disorder. Prior treatment for myelodysplastic syndrome (MDS) was allowed. In cycle 1, VEN was started at 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28. In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28. LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle. Preliminary efficacy was assessed as the overall response rate (ORR, which included complete remission [CR], CR with incomplete blood count recovery [CRi], and partial remission [PR]). Adverse events (AEs) and laboratory values were monitored. Exploratory analysis of biomarkers (eg, cytogenetics, molecular markers) was performed to identify potential predictors of clinical outcomes. Results: Data cutoff was May 30, 2017. All 71 patients were enrolled ≥1 year prior (46 [65%] male; median age, 74 years [range, 66-87 years]): 10 received VEN 800 mg and 61 received VEN 600 mg, the recommended phase 2 dose. Thirty-three patients (47%) had a history of antecedent hematologic disorder (AHD), most commonly MDS. Among 61 patients given VEN 600 mg, median time on VEN treatment was 6 months (range, Conclusions: The safety profile of VEN 600 mg/day plus LDAC was acceptable for elderly patients with treatment-naive AML who were ineligible for intensive chemotherapy. After ≥1 year of follow-up, the observed median OS was 11.4 months. This cohort included 44% (27/61) of patients with AHDs. Corelations of specified AML mutations with response and duration should be confirmed in later trials. Due to the observced CR/CRi rate of 62%, extended duration of response, and encouraging OS in a cohort of patients with particularly poor-risk features, the 600-mg dose of VEN combined with LDAC is being tested in an ongoing phase 3 study. Disclosures Wei: AbbVie, Celgene, Novartis, Amgen, Servier: Honoraria; AbbVie, Celgene, Servier: Research Funding; AbbVie, Celgene, Novartis, Amgen, Servier: Membership on an entity9s Board of Directors or advisory committees. Strickland: Boehringer-Ingelheim: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Novartis: Consultancy; Tolero: Consultancy; Astellas: Consultancy; CTI BioPharma: Consultancy; Baxalta: Consultancy. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Hou: Teva Oncology, Seattle Genetics: Speakers Bureau. Fiedler: Amgen, Pfizer: Research Funding; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance; Amgen: Patents & Royalties; Amgen, ARIAD/Incyte: Membership on an entity9s Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Consultancy. Walter: ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding. Chyla: Abbvie: Employment, Equity Ownership. Popovic: AbbVie: Employment, Equity Ownership. Fakouhi: AbbVie: Employment, Equity Ownership. Shah: AbbVie: Employment, Equity Ownership. Dunbar: AbbVie: Employment, Equity Ownership. Xu: AbbVie: Employment, Equity Ownership. Mabry: AbbVie: Employment, Equity Ownership. Hayslip: AbbVie: Employment, Equity Ownership.

Development of Guanfacine Extended-Release Dosing Strategies in Children and Adolescents with ADHD Using a Physiologically Based Pharmacokinetic Model to Predict Drug-Drug Interactions with Moderate CYP3A4 Inhibitors or Inducers.

BackgroundGuanfacine extended-release (GXR) is an orally administered, non-stimulant treatment for children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and is primarily metabolized by the 3A4 isozyme of cytochrome P450 (CYP3A4). The results of clinical pharmacokinetic (PK) studies indicate that guanfacine is sensitive to drug–drug interactions (DDIs) perpetrated by strong inhibitors and inducers of CYP3A4.ObjectiveThe aim was to provide guidance on the possible requirement for GXR dose adjustment in children and adolescents with ADHD by predicting DDIs following co-administration with moderate CYP3A4 inhibitors and inducers.MethodsA physiologically based PK model for GXR orally administered to healthy adults was developed based on physicochemical, in vitro and clinical PK data. The model was validated using clinical PK data for co-administration of GXR with ketoconazole (strong CYP3A4 inhibitor) or rifampicin (strong CYP3A4 inducer).ResultsModel predictions indicated that co-administration of GXR with the moderate CYP3A4 inhibitors erythromycin 500 mg three times a day or fluconazole 200 mg daily (q.d.) increased the guanfacine area under the plasma concentration–time curve (AUC) by 2.31-fold or 1.98-fold, respectively, compared with GXR monotherapy. The moderate CYP3A4 inducer efavirenz 400 mg or 600 mg q.d. was predicted to reduce guanfacine AUC to 58 or 33% of its value for GXR monotherapy, respectively.ConclusionWithout the requirement for additional clinical studies, the following GXR dose recommendations were developed and approved for US labeling for use in children and adolescents with ADHD: (1) decrease GXR to 50% of the usual target dose when it is co-administered with strong or moderate CYP3A4 inhibitors; (2) consider titrating GXR up to double the usual target dose over 1–2 weeks when it is co-administered with strong or moderate CYP3A4 inducers.

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.

A Drug-Drug Interaction Study of Ibrutinib with Moderate and Strong CYP3A Inhibitors in Patients with B-Cell Malignancy

Background:Ibrutinib, a potent inhibitor of Bruton’s tyrosine kinase, is indicated for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (including 17p deletion), and Waldenström’s macroglobulinemia. Because ibrutinib is extensively cleared by cytochrome P450 (CYP) 3A4, concomitant treatment with CYP3A inhibitors has been shown to increase ibrutinib exposure in healthy adults. However, sparse PK data from uncontrolled phase 2 studies with moderate CYP3A inhibitors showed a lower magnitude of drug-drug interactions (DDI) than observed in studies with healthy subjects or in silico simulations under nonfasted conditions (data on file). This phase 1 study was conducted to evaluate potential DDIs between ibrutinib and CYP3A inhibitors in patients with B-cell malignancies and to confirm recommended dose adjustments.Methods: This was an open-label, multicenter, DDI study of ibrutinib with erythromycin (moderate CYP3A inhibitor) and voriconazole (strong CYP3A inhibitor) in patients (≥ 18 years) with relapsed/refractory B-cell malignancy. During the first treatment cycle, patients received an oral dose of 560 mg ibrutinib on days 1-4 (steady-state) and days 14-18. On days 5-13 and 19-27, the dose was reduced to 140 mg ibrutinib and combined with erythromycin (500 mg tid on days 5-11) and then with voriconazole (200 mg bid on days 19-25). On PK sampling days (days 4 [alone], 11 [with erythromycin], and 25 [with voriconazole]), ibrutinib was administered 30 min before a standard breakfast. On these PK sampling days, the morning doses of voriconazole and erythromycin were administered 1 hr prior to ibrutinib and together with ibrutinib, respectively.PK samples were taken pre- and up to 24 hr postdose; key PK parameters were summarized for ibrutinib, PCI-45227 (ibrutinib metabolite), erythromycin, and voriconazole. After completion of the DDI assessment during cycle 1, patients continued treatment with ibrutinib monotherapy at therapeutic doses. Safety was evaluated throughout the study.Results:All patients (N = 26) completed the PK assessments in cycle 1; 54% were men, and the median age was 65 years. The geometric mean ratio (GMR) for dose-normalized maximum concentration (Cmax) and area under the plasma concentration-time curve from time 0 to 24 hr (AUC24h) for ibrutinib was 3.35 and 2.99, respectively, when given in combination with erythromycin (Table). When ibrutinib was coadministered with voriconazole, the GMR for Cmax and AUC24h was 6.71 and 5.74, respectively (Table). Four out of 26 patients showed either no interaction between ibrutinib and erythromycin or a lower ibrutinib exposure (AUC ratios 0.27-0.99). Three of these 4 patients also displayed minimal interaction with voriconazole (AUC ratios 1.08-1.96); baseline ibrutinib AUCs for the 3 patients were at the high end of the range, indicating lower CYP3A abundance and thus less impact from CYP inhibition.Physiologically-based PK modeling under fed conditions predicted a 5.5- and 7.1-fold increase in the GMR for ibrutinib Cmax and AUC, respectively, when dosed with erythromycin and an increase of 6.3- and 7.6-fold, respectively, when dosed with voriconazole. The simulated interaction factor for voriconazole is contained in the 90% CI of the observed GMRs (borderline for AUC), whereas the model over-predicted Cmax and AUC by ~50% and ~130%, respectively.Treatment-emergent adverse events (TEAEs) were reported in 22/26 patients (85%); The most common TEAEs (all causality, ≥ 10% of patients) were diarrhea (27%); neutropenia (23%); abdominal pain, fatigue, pyrexia, and thrombocytopenia (15% each); anemia, dry mouth, cough, dyspnea, and hypertension (12% each). Drug-related TEAEs ≥ grade 3 were neutropenia (15.4%); hypertension (7.7%); and diarrhea, thrombocytopenia, herpes zoster, cough, dyspnea, atrial fibrillation, and cardiac failure (3.8% each).Conclusions:PK data indicate that 140 mg ibrutinib, when combined with a moderate or strong CYP3A inhibitor, achieved exposures generally consistent with those after a 560 mg dose given alone. Coadministration of 140 mg ibrutinib with erythromycin or voriconazole demonstrated an acceptable safety profile, and the adverse event profile was consistent with the ibrutinib safety profile at therapeutic doses. These findings support the 140 mg/day ibrutinib dose when given in combination with erythromycin or voriconazole. [Display omitted] Disclosuresde Jong:Janssen: Employment. Hellemans:Janssen: Employment, Equity Ownership. De Wilde:Janssen: Employment. Patricia:Janssen: Employment. Masterson:Janssen: Employment. Osmanov:Seattle Genetics: Research Funding. Cordoba:Janssen: Research Funding, Speakers Bureau. Panizo:Roche Pharmaceuticals: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. de Zwart:Janssen: Employment. Snoeys:Janssen: Employment, Equity Ownership. Chauhan:Janssen: Consultancy. Jiao:Janssen: Employment. Sukbuntherng:Pharmacyclics, LLC: Employment, Equity Ownership; Global Blood Therapeutics: Equity Ownership. Ouellet:Janssen: Employment.

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.

In Vitro and In Vivo Primary Metabolic Characterization of F18, a Novel Histone Deacetylase-6 (HDAC6) Inhibitor, Using UHPLC–QqQ–MS/MS and Q-TOF–MS Methods

F18, N-hydroxy-4-(2-methoxy-5-(methyl (2-methylquinazolin-4-yl) amino) phenoxy) butanamide, is a novel selective HDAC6 inhibitor with good antitumor activity. In the early drug development, drug-metabolism studies are a crucial and indispensable part. In this study, we proposed to evaluate the in vitro primary metabolism of F18 in phase Ι in liver microsomes from human, rat, dog, monkey and mouse and investigate the metabolite profile both in vitro and in vivo using LC–MS/MS methods. F18 showed high metabolic stability in human, rat, dog, monkey and mouse liver microsomes over 120 min, with t 1/2 >8 h in human, rat, and dog, and t 1/2 100 μM), was a moderate inhibitor of CYP3A4 (IC50 = 1.63 μM) and had negligible effects on CYP3A1/2 activity in rats. The results will be valuable in understanding drug–drug interactions (DDI) when F18 is co-administered with other drugs. The metabolites of F18 were investigated in rat plasma, urine, feces and different liver microsomes in NADPH samples, yielding at least 11 metabolites in these biological samples. The prominent metabolic pathways were de-methylation, de-amination, de-oxidation and O-glucuronidation. In summary, this work provides the first clues regarding F18 metabolism, providing important information for comprehensive understanding of F18 metabolites.

Effects of Lemon and Seville Orange Juices on the Pharmacokinetic Properties of Sildenafil in Healthy Subjects.

PurposeSeveral severe drug interactions have been reported when sildenafil, a potent drug for the treatment of erectile dysfunction, is co-administered with drugs or herbal remedies that inhibit cytochrome P450 (CYP) 3A4. This study evaluates the effects of two citrus fruit juices, lemon and Seville orange, on the pharmacokinetics of sildenafil in male healthy subjects following a single oral dose.MethodsWe conducted an open-label, three-way crossover study in nine healthy male volunteers. Participants received a single oral dose of sildenafil (50 mg) after pretreatment with 250 mL of either water (control), undiluted lemon juice, or Seville orange juice for 3 consecutive days. All subjects were monitored for adverse effects during the study period. Plasma samples were collected for 12 h after dosing and analyzed for sildenafil concentration.ResultsCompared with pretreatment with water, Seville orange juice significantly increased the area under the plasma concentration-time curve from time zero to infinity and the peak plasma concentration of sildenafil by 44 % (90 % confidence interval [CI] 30–60) and 18 % (90 % CI 108–129), respectively, without affecting the time to reach peak plasma concentration. Additionally, Seville orange juice significantly reduced the apparent oral clearance of sildenafil by 30 % (90 % CI 63–75) without affecting its elimination half-life. In contrast, lemon juice did not cause any significant alterations in the pharmacokinetics of sildenafil. There was no significant treatment-related adverse effects reported during the study.ConclusionsAlthough it is considered as a moderate CYP3A4 inhibitor, Seville orange only caused a mild increase in exposure to sildenafil after a single oral dose, without manifestation of any adverse effects. The enhanced bioavailability of sildenafil by Seville orange may be attributed to inhibition of its intestinal first-pass effect (CYP3A4 and or p-glycoprotein). Lemon juice, in contrast, had no effects on the pharmacokinetics of sildenafil.

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.

In Silico Predictions and In Vivo Results of Drug–Drug Interactions by Ketoconazole and Verapamil on AZD1305, a Combined Ion Channel Blocker and a Sensitive CYP3A4 Substrate

The objectives were to estimate and compare, in silico and in vivo, the effects of a strong and a moderate CYP3A4 inhibitor on AZD1305 pharmacokinetics. In silico, simulations were performed with the computer software Simcyp, and the predicted outcome was compared with the results observed in healthy male subjects. In silico, the geometric mean plasma exposure of AZD1305 + ketoconazole showed a 7.1-fold higher AUC and a 4.4-fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 1.9-fold higher AUC and a 1.7-fold higher Cmax compared with AZD1305 alone. In vivo, the plasma exposure of AZD1305 + ketoconazole showed a 7.7-fold higher AUC and a 4.8 -fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 2.2-fold higher AUC and a 2.0-fold higher Cmax compared with AZD1305 alone. The mean maximum QTcF increase from baseline was 407, 487, and 437 milliseconds for AZD1305, alone and in combination with verapamil or ketoconazole, respectively. Simcyp predicted the effects of ketoconazole and verapamil on the sensitive CYP3A4 substrate AZD1305 pharmacokinetics well. Both the in vivo study and the Simcyp predictions suggest a contraindication for strong CYP3A4 inhibitors and AZD1305 when given in combination.

Mechanistic understanding of the nonlinear pharmacokinetics and intersubject variability of simeprevir: A PBPK-guided drug development approach.

Simeprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, displays nonlinear pharmacokinetics (PK) at therapeutic doses. Using physiologically based PK modeling, various drug-drug interactions were simulated with simeprevir as victim drug to identify whether saturation of the predominant metabolic enzyme (CYP3A4) or the active hepatic transporters (organic anion-transporting polypeptide (OATP)1B1/3) could account for the nonlinear PK. Interactions with ritonavir, a strong CYP3A4 inhibitor that does not affect OATP (at 100 mg dose), erythromycin, a moderate CYP3A4 inhibitor, and efavirenz, a moderate CYP3A inducer that does not affect OATP, demonstrated the involvement of CYP3A4. Interaction studies with low-dose cyclosporine confirmed the role of OATP. The interplay between hepatic uptake and CYP3A4 metabolism was verified by simulations with rifampicin, a potent CYP3A4 inducer and OATP1B1/3 inhibitor, and maintenance doses of cyclosporine. Saturation of gut and liver metabolism by CYP3A4, and saturation of hepatic uptake by OATP1B1/3, seem to account for the observed nonlinear PK of simeprevir.

Determining the IC 50 Values for Vorozole and Letrozole, on a Series of Human Liver Cytochrome P450s, to Help Determine the Binding Site of Vorozole in the Liver.

Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [11C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [11C]-vorozole is binding to in the liver.

Population pharmacokinetics of naloxegol in a population of 1247 healthy subjects and patients.

Naloxegol, a polyethylene glycol conjugated derivative of the opioid antagonist naloxone, is in clinical development for treatment of opioid-induced constipation (OIC). The aim of the study was to develop a population pharmacokinetic model describing the concentration vs. time profile of orally administered naloxegol, and determine the impact of pre-specified demographic and clinical factors and concomitant medication on population estimates of apparent clearance (CL/F) and apparent central compartment volume of distribution (Vc /F). Analysis included 12,844 naloxegol plasma concentrations obtained from 1247 healthy subjects, patients with non-OIC and patients with OIC in 14 phase 1, 2b and 3 clinical studies. Pharmacokinetic analysis used the non-linear mixed effects modelling program. Goodness of fit plots and posterior predictive checks were conducted to confirm concordance with observed data. The final model was a two compartment disposition model with dual absorptions, comprising one first order absorption (ka1 4.56 h(-1) ) and one more complex absorption with a transit compartment (ktr 2.78 h(-1) ). Mean (SE) parameter estimates for CL/F and Vc /F, the parameters assessed for covariate effects, were 115 (3.41) l h(-1) and 160 (27.4) l, respectively. Inter-individual variability was 48% and 51%, respectively. Phase of study, gender, race, concomitant strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers, P-glycoprotein inhibitors or inducers, naloxegol formulation, baseline creatinine clearance and baseline opioid dose had a significant effect on at least one pharmacokinetic parameter. Simulations indicated concomitant strong CYP3A4 inhibitors or inducers had relevant effects on naloxegol exposure. Administration of strong CYP3A4 inhibitors or inducers had a clinically relevant influence on naloxegol pharmacokinetics.

Flibanserin: First agent for female sexual dysfunction

Flibanserin: First agent for female sexual dysfunction

Drug-Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir.

Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug–drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.

Palbociclib: A new breakthrough for advanced breast cancer

Palbociclib: A new breakthrough for advanced breast cancer