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The effect of posaconazole, a strong cytochrome P450 3A (CYP3A) inhibitor and commonly used antifungal agent, on the pharmacokinetic properties of venetoclax, a CYP3A substrate, was evaluated in patients with acute myeloid leukemia to determine the dose adjustments needed to manage this potential interaction. Twelve patients received 20- to 200-mg ramp-up treatment with oral venetoclax and 20 mg/m2 of intravenous decitabine on days 1 through 5, followed by 400 mg of venetoclax alone on days 6 through 20. On days 21 through 28, patients received 300 mg of posaconazole plus reduced doses of venetoclax (50 or 100 mg) to account for expected increases in venetoclax plasma concentrations. Blood samples were collected before dosing and up to 24 hours after the venetoclax dose on days 20 and 28. Compared with a venetoclax dose of 400 mg when administered alone (day 20), coadministration of venetoclax at a 50-mg dose with multiple doses of posaconazole increased mean venetoclax Cmax and AUC0–24 by 53% and 76%, respectively, whereas coadministration of venetoclax at a 100-mg dose with posaconazole increased mean venetoclax Cmax and AUC0–24 by 93% and 155%, respectively. When adjusted for different doses and nonlinearity, posaconazole was estimated to increase venetoclax Cmax and AUC0–24 by 7.1- and 8.8-fold, respectively. Both the 50- and 100-mg venetoclax doses administered with posaconazole were well tolerated. The results are consistent with inhibition of CYP3A-mediated metabolism of venetoclax. Posaconazole can be used for antifungal prophylaxis in patients with acute myeloid leukemia receiving venetoclax after reducing the venetoclax dose by at least 75%. ClinicalTrials.gov identifier: NCT02203773.

Venetoclax, a highly potent BCL‐2 inhibitor, is indicated for treatment of some hematologic malignancies as monotherapy, and/or in combination with other agents. Venetoclax pharmacokinetics has been extensively characterized in patients and healthy participants. After oral dosing, the median time to reach maximum plasma concentration ranged from 5 to 8 h and harmonic mean half‐life ranged from 14 to 18 h. Food increases venetoclax bioavailability by 3–5‐fold and venetoclax should be administered with food to ensure adequate and consistent bioavailability. Venetoclax is eliminated via cytochrome P450 (CYP)3A metabolism, and a negligible amount of unchanged drug is excreted in urine. Strong CYP3A/P‐glycoprotein inhibitors increased venetoclax exposures (AUC) by 1.44‐ to 6.90‐fold while a significant decrease (71%) has been observed when dosed with strong CYP3 inducers. Venetoclax does not inhibit or induce CYP enzymes or transporters. Venetoclax pharmacokinetics is not appreciably altered by age, weight, sex, but the exposure is up to twofold higher in participants from Asian countries. Mild‐to‐severe renal impairment or end‐stage renal disease do not alter venetoclax exposures, and venetoclax is not cleared by dialysis. Although mild‐to‐moderate hepatic impairment does not affect venetoclax exposures, twofold higher exposure was observed in subjects with severe hepatic impairment. Venetoclax exposure is comparable across patients with different hematologic malignancies and healthy participants. Overall, venetoclax exposure is only affected by food and CYP3A modulators and is only higher in Asian subjects and subjects with severe hepatic impairment. Venetoclax exposure–response relationships are malignancy‐dependent and can be different between monotherapy and combination therapy.

Telisotuzumab vedotin (Teliso‐V) is a c‐Met‐directed antibody‐drug conjugate that delivers a cytotoxic microtubule inhibitor monomethyl auristatin E (MMAE) payload to c‐Met‐expressing tumor cells. It received accelerated approval from the US FDA for the treatment of adults with locally advanced or metastatic non‐squamous non‐small cell lung cancer (NSCLC) with high c‐Met protein overexpression (≥ 50% of tumor cells with strong [3+] staining) at a dose of 1.9 mg/kg every 2 weeks (Q2W; maximum 190 mg for patients ≥ 100 kg) as an intravenous infusion. Population pharmacokinetic (PK) modeling used pooled data from a phase 1 (N = 35) and phase 2 study (N = 269) to describe the Teliso‐V conjugate and unconjugated MMAE PK and evaluate the impact of intrinsic and extrinsic factors on exposures in patients with solid tumors. Body weight, race, albumin, and anti‐drug antibody status were identified as significant covariates on Teliso‐V conjugate clearance, but did not result in clinically meaningful changes in exposure. The exposure‐response evaluations for efficacy (based on the pivotal phase 2 study) showed significant correlations between conjugate exposure and overall response rates. Higher conjugate exposures were also correlated with improved progression‐free survival and overall survival, demonstrating meaningful clinical benefit with the 1.9 mg/kg Q2W dosing regimen. Exposure‐safety evaluations showed significant relationships between conjugate exposures and grade ≥ 2 and grade ≥ 3 peripheral neuropathy, and grade ≥ 2 corneal epitheliopathy. Unconjugated MMAE payload exposures were correlated with a greater probability of grade ≥ 3 treatment‐emergent adverse events. The 1.9 mg/kg Q2W dose maximized efficacy while balancing adverse events in patients with c‐Met overexpressing NSCLC. Study Highlights What is the current knowledge on the topic? ○Teliso‐V has compelling efficacy at the 1.9 mg/kg every 2‐week regimen in c‐Met overexpressing non‐squamous non‐small cell lung cancer (NSCLC). Population pharmacokinetic (PK) analyses integrating data across trials, including covariate assessments and ER evaluations from the pivotal LUMINOSITY phase 2 study to inform dosing, have not been published to date. What question did this study address? ○This analysis characterized the PK of Teliso‐V conjugate and unconjugated MMAE and assessed the impact of intrinsic and extrinsic factors on PK. ER analyses for efficacy and safety were used to evaluate the dosing regimen of Teliso‐V. What does this study add to our knowledge? ○Positive relationships between higher Teliso‐V conjugate exposure and efficacy in the LUMINOSITY phase 2 study support the benefit of Teliso‐V 1.9 mg/kg every 2 weeks in patients with c‐Met protein overexpressing NSCLC as the approved dose. How might this change drug discovery, development, and/or therapeutics? ○The Teliso‐V approved dose of 1.9 mg/kg Q2W is appropriate for the approved indication. The findings indicate that for Teliso‐V, efficacy is correlated with ADC exposure, while safety is influenced by both ADC and MMAE payload exposure. Higher exposures correlate with improved efficacy but also increased safety risks, underscoring the need to carefully balance therapeutic benefit with tolerability to achieve optimal clinical efficacy with manageable safety for Teliso‐V.

Navitoclax, an oral small molecule BCL‐XL/BCL‐2 inhibitor evaluated in myelofibrosis, was assessed through integrated PK/PD modeling to guide starting dose and dose‐reduction decisions when combined with ruxolitinib. An integrated sequential PK/PD model was developed to describe the relationships between navitoclax and ruxolitinib exposure, platelet count, and spleen volume. Simulations were conducted to assess spleen volume reductions of ≥ 35% at week 24 (SVR35W24) and incidences of ≥ grade 3 or grade 4 thrombocytopenia. The population PKs were adequately characterized by two‐compartment models, and the subsequent integrated PK/PD model adequately described the platelet and spleen volume data. Model simulations indicated that the incidence of ≥ grade 3 or grade 4 thrombocytopenia during a weekly ramp‐up from navitoclax 100 to 200 mg once daily (QD) was similar to that predicted with a flat 200 mg QD starting dose. Simulations suggested that reducing doses of navitoclax by 25 mg for patients with baseline platelet counts ≤ 150 × 109/L (starting at 100 mg) and by 50 mg, with an additional 25 mg if needed, for those > 150 × 109/L (starting at 200 mg) effectively minimized ≥ grade 3 thrombocytopenia while maintaining SVR35W24. Integrated PK/PD model simulations suggested that a flat starting dose of navitoclax 200 mg for baseline platelets > 150 × 109/L, and 100 mg for ≤ 150 × 109/L with ruxolitinib minimized thrombocytopenia risk while maintaining efficacy. Dose reductions of 25 mg for the 100 mg start and 50 mg (plus 25 mg if needed) for the 200 mg start optimized the benefit–risk balance. Study Highlights What is the current knowledge on the topic? ○Navitoclax, a small molecule BCL‐XL/BCL‐2 inhibitor, was investigated for use in adults with primary or secondary myelofibrosis. Thrombocytopenia was a common adverse event that led to dose reductions in a previous phase 2 study. What question did this study address? ○This analysis developed pharmacokinetic and pharmacodynamic models to evaluate the effect of navitoclax in combination with ruxolitinib on platelet count and spleen volume dynamics to justify a starting dose of navitoclax and provide guidance on dose reductions based on platelet counts. What does this study add to our knowledge? ○The integrated model simulations suggested that a flat starting dose of navitoclax 200 mg for baseline platelets > 150 × 109/L and 100 mg for ≤ 150 × 109/L with ruxolitinib minimized thrombocytopenia risk while maintaining efficacy. Additionally, dose reductions of 25–50 mg, depending on the starting dose, may further optimize the benefit–risk balance in this patient population. How might this change drug discovery, development, and/or therapeutics? ○This work supported using baseline platelet counts to guide navitoclax dosing in combination with ruxolitinib in patients with myelofibrosis, helping to minimize thrombocytopenia and maintain treatment efficacy and continuity.

The development of direct-acting antiviral (DAA) agents has reinvigorated the treatment of hepatitis C virus infection. The availability of multiple DAA agents and drug combinations has enabled the transition to interferon-free therapy that is applicable to a broad range of patients. However, these DAA combinations are not without drug–drug interactions (DDIs). As every possible DDI permutation cannot be evaluated in a clinical study, guidance is needed for healthcare providers to avoid or minimize drug interaction risk. In this review, we evaluated the DDI potential of the novel three-DAA combination of ombitasvir, paritaprevir, ritonavir, and dasabuvir (the 3D regimen) with more than 200 drugs representing 19 therapeutic drug classes. Outcomes of these DDI studies were compared with the metabolism and elimination routes of prospective concomitant medications to develop mechanism-based and drug-specific guidance on interaction potential. This analysis revealed that the 3D regimen is compatible with many of the drugs that are commonly prescribed to patients with hepatitis C virus infection. Where interaction is possible, risk can be mitigated by paying careful attention to concomitant medications, adjusting drug dosage as needed, and monitoring patient response and/or clinical parameters.

Background and Aims The three direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D regimen) is approved for treatment of hepatitis C virus (HCV) genotype 1 infection. Drug–drug interaction (DDI) studies of the 3D regimen and commonly used medications were conducted in healthy volunteers to provide information on coadministering these medications with or without dose adjustments. Methods Three phase I studies evaluated DDIs between the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily + dasabuvir 250 mg twice daily) and hydrocodone bitartrate/acetaminophen (5/300 mg), metformin hydrochloride (500 mg), diazepam (2 mg), cyclobenzaprine hydrochloride (5 mg), carisoprodol (250 mg), or sulfamethoxazole/trimethoprim (SMZ/TMP) (800/160 mg twice daily), all administered orally. DDI magnitude was determined using geometric mean ratios and 90 % confidence intervals for the maximum plasma concentration ( C max ) and area under the plasma concentration–time curve (AUC). Results Changes in exposures ( C max and AUC geometric mean ratios) of acetaminophen, metformin, sulfamethoxazole, trimethoprim, and diazepam were ≤25 % upon coadministration with the 3D regimen. The C max and AUC of nordiazepam, an active metabolite of diazepam, increased by 10 % and decreased by 44 %, respectively. Exposures of cyclobenzaprine and carisoprodol decreased by ≤40 and ≤46 %, respectively, whereas exposures of hydrocodone increased up to 90 %. Ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures changed by ≤25 %, except for a 37 % decrease in paritaprevir C max with metformin and a 33 % increase in dasabuvir AUC with SMZ/TMP. Conclusions Acetaminophen, metformin, sulfamethoxazole, and trimethoprim can be coadministered with the 3D regimen without dose adjustment. Higher doses may be needed for diazepam, cyclobenzaprine, and carisoprodol based on clinical monitoring. A 50 % lower dose and/or clinical monitoring should be considered for hydrocodone. No dose adjustment is necessary for the 3D regimen.

The immunosuppressive agents sirolimus and everolimus are sensitive CYP3A4 substrates with narrow therapeutic index. Ritonavir is a strong CYP3A inhibitor. A phase 1 study was conducted to evaluate the pharmacokinetics, safety, and tolerability of the co‐administration of sirolimus or everolimus with the ritonavir‐containing 3D regimen of the direct‐acting antiviral agents ombitasvir, ritonavir‐boosted paritaprevir, and dasabuvir in healthy subjects. This study had two independent arms, each with a two‐period, single‐sequence, crossover study design. A single dose of sirolimus 2 mg (N = 12) or everolimus 0.75 mg (N = 12) was administered in Period 1. In Period 2, multiple doses of the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily and dasabuvir 250 mg twice daily) were administered for 34 or 28 days, with a single dose of sirolimus 0.5 mg or everolimus 0.75 mg co‐administered on Day 15. Following co‐administration with the 3D regimen, the sirolimus dose‐normalized maximum observed blood concentration (Cmax) and area under the blood concentration–time curve from time zero to infinity (AUCinf) increased to 6.4‐fold and 38‐fold, respectively. Following co‐administration with the 3D regimen, the everolimus Cmax and AUCinf increased to 4.7‐fold and 27‐fold, respectively. Sirolimus and everolimus half‐lives increased from 96 to 249 h, and 42 to 118 h, respectively. There were no major safety or tolerability issues in this study. The ritonavir‐containing 3D regimen resulted in a significant increase in sirolimus or everolimus exposure, consistent with the known strong inhibitory effect of ritonavir on CYP3A requiring dose and/or frequency modification when co‐administered with each other. When co‐administered with the ritonavir‐containing 3D regimen, sirolimus and everolimus exposures (AUC) increased to 38‐fold and 27‐fold, respectively. The study results can be used to guide dose recommendation for sirolimus or everolimus when co‐administered with ritonavir‐containing regimens.

PurposeVenetoclax, a targeted anticancer agent approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, is a substrate of cytochrome P450 (CYP) 3A enzyme (CYP3A4). Posaconazole, commonly used to prevent invasive fungal infections in neutropenic patients with hematological malignancies, potently inhibits CYP3A4. The purpose of this evaluation was to predict venetoclax exposures following co-administration of posaconazole at doses not previously studied clinically.MethodsTwo physiologically based pharmacokinetic (PBPK) models were developed for posaconazole based on published parameters, one for an oral suspension and another for delayed released tablets. Parameter optimization, guided by sensitivity analyses, was conducted such that the models could replicate clinical exposures of posaconazole and drug–drug interactions with sensitive CYP3A substrates including venetoclax. The clinically verified posaconazole PBPK models were then utilized to predict DDI with a previously published venetoclax PBPK model at clinically relevant dosing scenarios.ResultsThe posaconazole PBPK models predicted posaconazole exposure and DDI related fold changes with acceptable prediction errors for both posaconazole formulations. The model predicted exposures of venetoclax, when co-administered with a 300 mg QD dose of delayed release tablets of posaconazole, were in concordance with observed data. Increasing the posaconazole dose to 500 mg QD increased venetoclax exposures by about 12% relative to 300 mg QD, which were still within the venetoclax safe exposure range.ConclusionsThe posaconazole PBPK models were developed and clinically verified. Predictions using the robust PBPK model confirmed the venetoclax label recommendation of 70 mg in the presence of posaconazole at doses up to 500 mg QD.

The 2 direct-acting antiviral combination (2D) of ombitasvir and paritaprevir (coadministered with ritonavir) is being evaluated for the treatment of chronic hepatitis C virus infection in Japan. Ursodeoxycholic acid (UDCA) and glycyrrhizin (GCR) are hepatoprotective agents widely used in Japan. A drug-drug interaction (DDI) study was conducted to guide dosing recommendations for UDCA and GCR when coadministered with the 2D regimen. DDIs between the 2D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg orally once daily) and UDCA (50 mg orally 3 times daily) or GCR (80 mg intravenously once daily) were evaluated in a 2-arm, multiple-dose study in 24 Japanese healthy subjects under fed conditions. Pharmacokinetic and safety evaluations were performed when UDCA or GCR and the 2D regimen were administered alone and during coadministration. Exposures from coadministration of the 2D regimen plus UDCA or GCR versus the 2D regimen, UDCA, or GCR alone were compared using repeated-measures analyses of natural logarithms of the maximum plasma concentration (Cmax) and area under the curve (AUC). After coadministration of the 2D regimen and UDCA, steady-state exposures (Cmax and AUC) of ombitasvir, paritaprevir, and ritonavir showed a ≤9% change, and UDCA exposures showed a ≤20% change compared with administration alone. When the 2D regimen and GCR were coadministered, steady-state exposures of ombitasvir, paritaprevir, and ritonavir were not affected (≤9% change), GCR AUC increased by 49%, and GCR Cmax was unaffected (<1% change). No dose adjustment is needed for UDCA, GCR, or the 2D regimen when UDCA or GCR is coadministered with the 2D regimen in hepatitis C virus–infected patients under fed conditions. Clinical monitoring of patients using GCR is recommended due to an approximately 50% increase in GCR AUC when coadministered with the 2D regimen.

Background and Objective Navitoclax, an orally bioavailable B-cell lymphoma-2 (Bcl-2) family protein inhibitor, inhibits antiapoptotic Bcl-2 family proteins (with high affinity to Bcl-XL, Bcl-2, and Bcl-W). Navitoclax in combination with ruxolitinib has been investigated to treat patients with myelofibrosis (MF). Methods Since navitoclax undergoes hepatic metabolism, we evaluated the pharmacokinetics (PK) and safety of single-dose navitoclax 50 mg in a phase 1 study in participants with mild ( N = 6), moderate ( N = 6), or severe ( N = 1) hepatic impairment and matched participants with normal hepatic function ( N = 7). All participants in this study were enrolled per Child–Pugh classification, with demographics matched per age, weight, and race. Results Navitoclax maximum plasma concentration ( C max ), area under the plasma concentration–time curve for time zero to infinity (AUC 0-∞ ), and terminal elimination half-life (t 1/2 ) in participants with mild or moderate hepatic impairment were comparable to participants with normal hepatic function. The change in C max and AUC 0–∞ values in participants with mild and moderate hepatic impairment were within 25% of normal hepatic function. Overall, 2/20 (10%) participants receiving a 50 mg single dose reported grade 1 treatment-emergent adverse events of nausea ( N = 1) and diarrhea ( N = 1). Conclusions In summary, no new safety issues were identified. On the basis of the pharmacokinetic results, no dose adjustment is required for patients with MF with mild or moderate hepatic impairment.