Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety.

Venetoclax, a potent BCL-2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure-response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression-free survival [PFS] and overall survival [OS]) as well as safety (treatment-emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment-emergent adverse effects) was evaluated. In the t(11;14)-positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant (p < 0.05) relationship with exposure. Evaluation of the exposure-safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUCavg ) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment-emergent adverse events or any grade serious treatment-emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)-positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013.

Venetoclax pharmacokinetics in participants with end-stage renal disease undergoing haemodialysis.

AIMS: Renal insufficiency is a common comorbidity in patients with haematological malignancies. This study aimed to assess how end-stage renal disease (ESRD) might affect the pharmacokinetics of venetoclax, a Bcl-2 inhibitor, in participants with ESRD undergoing haemodialysis. METHODS: Venetoclax was administered as a single 100-mg dose to 6 female participants with ESRD (estimated glomerular filtration rate <15 mL/min) both prior to haemodialysis and between haemodialysis days and 7 healthy female participants with normal renal function (estimated glomerular filtration rate >90 mL/min). Intensive pharmacokinetic and protein binding samples were collected from all participants. Arterial and venous samples were collected from ESRD participants during haemodialysis to assess the effect of haemodialysis on venetoclax pharmacokinetics. Pharmacokinetic parameters were estimated using noncompartmental methods. RESULTS: There was no difference in plasma venetoclax concentrations between arterial and venous samples, suggesting that haemodialysis did not affect the pharmacokinetics of venetoclax. The fraction unbound (fu ) of venetoclax was ~2-fold higher for participants with ESRD compared to participants with normal renal function. The unbound maximum plasma concentration and area under the plasma concentration-time curve from time 0 to 48 h were comparable between ESRD and normal function groups. The mean half-life ranged from 10.4 to 12.2 h across groups, demonstrating that ESRD did not affect the half-life of venetoclax. No new safety signals were observed during this study. CONCLUSION: ESRD and dialysis do not alter unbound venetoclax plasma concentrations. No pharmacokinetics driven dose adjustment is needed for patients with renal insufficiency.

Effects of chronic kidney disease stage 4, end-stage renal disease, or dialysis on the plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir in patients with chronic HCV infection: pharmacokinetic analysis of the phase 3 RUBY-I and RUBY-II trials.

PURPOSE: To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies. METHODS: Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (Ctrough) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data. RESULTS: The AUC values of ombitasvir, paritaprevir, ritonavir, and dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state Ctrough values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values. CONCLUSION: Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment. TRIAL REGISTRATION: Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II).

Use of depth of response to predict progression-free survival in relapsed or refractory multiple myeloma: Evaluation of results from 102 clinical trials.

Progression-free survival (PFS) is the standard endpoint for demonstration of clinical effectiveness of novel therapies in relapsed or refractory multiple myeloma (RRMM). However, the long evaluation times for PFS limits its usefulness in the development of new therapies. Therefore, the objective of this analysis was to determine the relationship between response rates and median PFS in RRMM. A database was systematically developed from 268 identified RRMM trials reported from 1999 to 2016. Evaluated covariates for the relationship between response rates and PFS included age, sex, drug class(es), and number of drug classes. One-hundred two (102) trials involving 136 cohorts were included in the meta-analysis, representing 13 322 patients in total. Regression analysis using response rates and median PFS indicated that the correlation between very good partial response (VGPR) or better and median PFS was higher (R2  = 0.63) than the separately analyzed correlations between clinical benefit, overall response, or complete response rate and median PFS (R2  = 0.47 - 0.52). Subsequent covariate analysis revealed that treatment with an immunomodulatory imide drug (IMiD) further improved the relationship (R2  = 0.69), with a longer median PFS at a given VGPR or better rate when at least 1 drug treatment was an IMiD. Number of drug classes was not found to alter this relationship. In conclusion, VGPR or better rate can be used to predict the median PFS, with adjustment for the additional PFS provided by an IMiD.

Clinical evaluation of P-glycoprotein inhibition by venetoclax: a drug interaction study with digoxin.

1. Venetoclax is a novel, small molecule B-cell lymphoma-2 (BCL-2) inhibitor that has demonstrated clinical efficacy in a variety of haematological malignancies. Since venetoclax is an inhibitor of P glycoprotein (P-gp) transporter, a study was conducted in healthy, female volunteers to evaluate the effect of venetoclax on the pharmacokinetics of digoxin, a P-gp probe substrate. 2. Volunteers received a single oral dose of digoxin (0.5 mg) with or without a single oral dose of venetoclax (100  mg). Serial blood samples were obtained for pharmacokinetic assessments of digoxin and venetoclax and serial urine samples were obtained for measurement of digoxin concentrations. Safety was assessed throughout the study. 3. Coadministration of digoxin and venetoclax increased digoxin maximum observed plasma concentration (Cmax) by 35% and area under the plasma-concentration time curve (AUC0-∞) by 9%. Digoxin half-life, renal clearance and the fraction excreted unchanged in urine remained relatively similar. The results of this study indicate that venetoclax can increase the concentrations of P-gp substrates. Narrow therapeutic index P-gp substrates should be administered six hours prior to venetoclax to minimise the potential interaction.

Guiding dose adjustment of amlodipine after co-administration with ritonavir containing regimens using a physiologically-based pharmacokinetic/pharmacodynamic model.

Amlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug-drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously. A novel physiologically-based pharmacokinetic (PBPK) model was developed for amlodipine, and the model was verified using published clinical PK and DDI data. The verified amlodipine PBPK model was linked to a pharmacodynamics model that describes changes in systolic blood pressure (SBP) during and after co-administration with RTV. The magnitude and time course of RTV effects on amlodipine plasma exposures and SBP were evaluated, to provide guidance on dose adjustment of amlodipine during and after co-administration with RTV-containing regimens. Model simulations suggested that the increase in amlodipine's plasma exposure by RTV diminishes by approximately 80% within 5 days after the last dose of RTV. PBPK simulations suggested that resuming a full dose of amlodipine [5 mg once daily (QD)] immediately after RTV's last dose would decrease daily average SBP by a maximum of 3.3 mmHg, while continuing with the reduced dose (2.5 mg QD) for 5 days after the last dose of RTV would increase daily average SBP by a maximum of 5.8 mmHg. Based on these results, either approach of resuming amlodipine's full dose could be appropriate when combined with appropriate clinical monitoring.

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy.

Venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified. The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose.

Population pharmacokinetics of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin in hepatitis C virus genotype 1 infection: analysis of six phase III trials.

AIM: The aim of the current study was to characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir and dasabuvir) and adjunctive ribavirin, and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection. METHODS: Pharmacokinetic data from six phase III studies and one phase II study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 weeks or 24 weeks were characterized using separate population pharmacokinetic models, built using each component of the regimen from nonlinear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks and bootstrap evaluations. RESULTS: The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, n = 2348) and ribavirin (n = 1841) adequately described their respective plasma concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive ability. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, gender, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance. CONCLUSION: The population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase II and III HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen.

Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir.

The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT02356562 and NCT02292719.).

Drug Interactions with the Direct-Acting Antiviral Combination of Ombitasvir and Paritaprevir-Ritonavir.

The two direct-acting antiviral (2D) regimen of ombitasvir and paritaprevir (administered with low-dose ritonavir) is being developed for treatment of genotype subtype 1b and genotypes 2 and 4 chronic hepatitis C virus (HCV) infection. Drug-drug interactions were evaluated in healthy volunteers to develop dosing recommendations for HCV-infected subjects. Mechanism-based interactions were evaluated for ketoconazole, pravastatin, rosuvastatin, digoxin, warfarin, and omeprazole. Interactions were also evaluated for duloxetine, escitalopram, methadone, and buprenorphine-naloxone. Ratios of geometric means with 90% confidence intervals for the maximum plasma concentration and the area under the plasma concentration-time curve were estimated to assess the magnitude of the interactions. For most medications, coadministration with the 2D regimen resulted in a <50% change in exposures. Ketoconazole, digoxin, pravastatin, and rosuvastatin exposures increased by up to 105%, 58%, 76%, and 161%, respectively, and omeprazole exposures decreased by approximately 50%. Clinically meaningful changes in ombitasvir, paritaprevir, or ritonavir exposures were not observed. In summary, all 11 medications evaluated can be coadministered with the 2D regimen, with most medications requiring no dose adjustment. Ketoconazole, digoxin, pravastatin, and rosuvastatin require lower doses, and omeprazole may require a higher dose. No dose adjustment is required for the 2D regimen.

Pharmacokinetics of Tacrolimus and Cyclosporine in Liver Transplant Recipients Receiving 3 Direct-Acting Antivirals as Treatment for Hepatitis C Infection.

BACKGROUND: Interactions between tacrolimus and cyclosporine (CSA) and the 3 direct-acting antiviral regimen (3D) of ombitasvir, paritaprevir/ritonavir, and dasabuvir necessitate a priori dose adjustments for the immunosuppressants to achieve desired levels. Modeling and simulations based on data in healthy subjects predicted that tacrolimus 0.5 mg every 7 days or 0.2 mg every 3 days, and CSA at one-fifth the total daily dose administered once daily, would achieve desired trough concentrations (Ctrough) during 3D treatment. The success of these dosing recommendations was evaluated by analyzing pharmacokinetic data from liver transplant recipients in the CORAL-I study. METHODS: A population pharmacokinetic model was developed using tacrolimus dosing and Ctrough data before and during 3D treatment (n = 29). The model was used to simulate various tacrolimus dosing regimens and predict tacrolimus concentration-time profiles during 3D treatment. CSA Ctrough data before and during 3D treatment (n = 5) were also summarized. RESULTS: A one-compartment model with first-order absorption adequately described tacrolimus pharmacokinetic profiles during the first 4 weeks of 3D treatment. Estimated tacrolimus Ctrough values (median; interquartile range) before and during 3D treatment were comparable (5.7 ng/mL; 4.9-6.5 ng/mL versus 5.2 ng/mL; 4.2-6.3 ng/mL, respectively). Based on simulations, in a patient with a starting Ctrough of 6 ng/mL, 0.5 mg tacrolimus every 7 or 14 days or 0.2 mg tacrolimus every 3 days will result in Ctrough levels of 6-9 ng/mL, 4-6 ng/mL, and 6-10 ng/mL, respectively, during 3D treatment. For CSA, Ctrough values (median; interquartile range) before and during 3D treatment were comparable (126 ng/mL; 94-140 ng/mL versus 104 ng/mL; 82-140 ng/mL). CONCLUSIONS: Observed data for tacrolimus and CSA in liver transplant recipients confirm that the recommended dosing strategies are valid and therapeutic levels of immunosuppression can be maintained during 3D treatment.

Pharmacokinetics and safety of co-administered paritaprevir plus ritonavir, ombitasvir, and dasabuvir in hepatic impairment.

BACKGROUND & AIMS: Paritaprevir, ombitasvir, and dasabuvir are direct-acting antivirals for treatment of chronic hepatitis C virus (HCV) infection. The aim of this study was to characterize the effects of mild, moderate, and severe hepatic impairment on the pharmacokinetics of these drugs. METHODS: HCV-negative subjects with normal hepatic function (n=7) or mild (Child-Pugh A, n=6), moderate (Child-Pugh B, n=6), or severe (Child-Pugh C, n=5) hepatic impairment received a single-dose of the combination of paritaprevir plus ritonavir (paritaprevir/r, 200/100 mg), ombitasvir (25 mg), and dasabuvir (400 mg). Plasma samples were collected through 144 hours after administration for pharmacokinetic assessments. RESULTS: Paritaprevir, ombitasvir, dasabuvir, and ritonavir exposures (maximal plasma concentration, C(max), and area under the concentration-time curve, AUC) were minimally affected in subjects with mild or moderate hepatic impairment. Differences in exposures between healthy controls and subjects with mild or moderate hepatic impairment were less than 35%, except for 62% higher paritaprevir AUC in subjects with moderate hepatic impairment. Paritaprevir and dasabuvir AUC were significantly higher in subjects with severe hepatic impairment (950% and 325%, respectively). However, ombitasvir AUC was 54% lower and ritonavir AUC was comparable. Adverse events included eye stye, insomnia, and pain from an infiltrated intravenous line. CONCLUSIONS: The changes observed in paritaprevir, ritonavir, ombitasvir, and dasabuvir exposures in subjects with mild or moderate hepatic impairment do not necessitate dose adjustment. Subjects with severe hepatic impairment had substantially higher paritaprevir and dasabuvir exposures.

Drug-drug interaction profile of the all-oral anti-hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir, and dasabuvir.

BACKGROUND & AIMS: Paritaprevir (administered with ritonavir, PTV/r), ombitasvir (OBV), and dasabuvir (DSV) are direct-acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection. Thirteen studies were conducted to characterize drug-drug interactions for the 3D regimen of OBV, PTV/r, and DSV and various medications in healthy volunteers to inform dosing recommendations in HCV-infected patients. METHODS: Mechanism-based drug-drug interactions were evaluated for gemfibrozil, ketoconazole, carbamazepine, warfarin, omeprazole, digoxin, pravastatin, and rosuvastatin. Drug-drug interactions with medications commonly used in HCV-infected patients were evaluated for amlodipine, furosemide, alprazolam, zolpidem, duloxetine, escitalopram, methadone, buprenorphine/naloxone, and oral contraceptives. Ratios of geometric means with 90% confidence intervals for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were used to determine the magnitude of interaction. RESULTS: Coadministration with the 3D regimen of OBV, PTV/r, and DSV resulted in a <2-fold change in mean Cmax and AUC for most medications and the DAAs, indicating minimal to modest interactions. Carbamazepine decreased PTV, ritonavir, and DSV exposures substantially, while gemfibrozil increased DSV exposures substantially. Although coadministration with ethinyl estradiol-containing contraceptives resulted in elevated alanine aminotransferase levels, coadministration with a progestin-only contraceptive did not. CONCLUSIONS: The majority of medications can be coadministered with the 3D regimen of OBV, PTV/r, and DSV without dose adjustment, or with clinical monitoring or dose adjustment. Although no dose adjustment is necessary for the 3D regimen when coadministered with 17 of the 20 medications, coadministration with gemfibrozil, carbamazepine, or ethinyl estradiol-containing contraceptives is contraindicated.

Clinical pharmacokinetics and pharmacodynamics of venetoclax, a selective B-cell lymphoma-2 inhibitor.

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.

Pharmacokinetics and immunogenicity of eftozanermin alfa in subjects with previously-treated solid tumors or hematologic malignancies: results from a phase 1 first-in-human study.

PURPOSE: Eftozanermin alfa is a second-generation tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist that enhances death receptor 4/5 clustering on tumor cells to induce apoptosis. We report the pharmacokinetics and immunogenicity of eftozanermin alfa administered intravenously to 153 adults with previously-treated solid tumors or hematologic malignancies from the first-in-human, open-label, dose-escalation and dose-optimization study. METHODS: Dose escalation evaluated eftozanermin alfa monotherapy 2.5-15 mg/kg on Day 1 or Days 1/8 of a 21-day cycle. Dose optimization evaluated eftozanermin alfa monotherapy or combination therapy with either oral venetoclax 400-800 mg daily (eftozanermin alfa 1.25-7.5 mg/kg Days 1/8/15 of a 21-day cycle) or chemotherapy (eftozanermin alfa 3.75 or 7.5 mg/kg Days 1/8/15/22 of a 28-day cycle and FOLFIRI regimen [leucovorin, 5-fluorouracil, and irinotecan] with/without bevacizumab on Days 1/15 of a 28-day cycle). RESULTS: Systemic exposures (maximum observed concentration [Cmax] and area under the concentration-time curve [AUC]) of eftozanermin alfa were approximately dose-proportional across the entire dose escalation range with minimal to no accumulation in Cycle 3 versus Cycle 1 exposures. Comparable exposures and harmonic mean half-lives (35.1 h [solid tumors], 31.3 h [hematologic malignancies]) were observed between malignancy types. Exposures (dose-normalized Cmax and AUC) in Japanese subjects were similar to non-Japanese subjects. Furthermore, eftozanermin alfa/venetoclax combination therapy did not have an impact on the exposures of either agent. Treatment-emergent anti-drug antibodies were observed in 9.4% (13/138) of subjects. CONCLUSIONS: The study results, including a pharmacokinetic profile consistent with weekly dosing and low incidence of immunogenicity, support further investigation of eftozanermin alfa. TRIAL REGISTRATION ID: NCT03082209.

Impact of Multiple Concomitant CYP3A Inhibitors on Venetoclax Pharmacokinetics: A PBPK and Population PK-Informed Analysis.

Venetoclax is an approved, orally bioavailable, B-cell lymphoma type 2 (BCL-2) inhibitor that is primarily metabolized by cytochrome P450 3A (CYP3A). Polypharmacy is common in patients undergoing treatment for hematological malignancies such as acute myeloid leukemia or chronic lymphocytic leukemia, and although venetoclax exposure has been well characterized with 1 concomitant CYP3A inhibitor, complex drug-drug interactions (DDIs) involving more than 1 inhibitor have not been systematically evaluated. Here, we aimed to describe the potential impact of multiple concomitant CYP3A inhibitors on venetoclax pharmacokinetics (PK) using physiologically based pharmacokinetic (PBPK) and population PK modeling. The modeling approaches were informed by clinical data in the presence of single or multiple CYP3A inhibitors, and the effects of 1 or more inhibitors were systematically considered within these modeling frameworks. The PBPK modeling approach was independently validated against clinical data involving more than 1 CYP3A inhibitor along with CYP3A substrates other than venetoclax. Both approaches indicated that combining a strong CYP3A inhibitor with another competitive CYP3A inhibitor does not seem to result in any additional increase in venetoclax exposure, beyond what would be expected with a strong inhibitor alone. This suggests that the current dose reductions recommended for venetoclax would be appropriate even when 2 or more CYP3A inhibitors are taken concomitantly. However, the results indicate that the involvement of time-dependent inhibition might lead to additional inhibitory effects over and above the effect of a single strong CYP3A inhibitor. Thus, the clinical management of such interactions must consider the underlying mechanism of the interactions.

Pharmacokinetic analysis after implantation of everolimus-eluting self-expanding stents in the peripheral vasculature.

BACKGROUND: A novel self-expanding drug-eluting stent was designed to release everolimus 225 µg/cm(2) to prevent restenosis following peripheral arterial intervention. The purpose of this study was to measure the pharmacokinetic profile of everolimus following stent implantation. METHODS: One hundred four patients with symptomatic peripheral arterial disease underwent implantation of everolimus-eluting stents in the femoropopliteal arteries. In a prespecified subset of 26 patients, blood samples for assay of everolimus content were collected prior to stent implantation, at 1, 4, and 8 hours postprocedure, prior to discharge, and at 1 month postprocedure. RESULTS: A total of 39 stents, ranging from 28 mm to 100 mm in length, were implanted in 26 patients, resulting in a total delivered everolimus dose range of 3.0 to 7.6 mg. Following the procedure, the maximum observed everolimus blood concentrations (C(max)) varied from 1.83 ± 0.05 ng/mL after implantation of a single 80-mm stent to 4.66 ± 1.78 ng/mL after implantation of two 100-mm stents. The mean time to peak concentration (T(max)) varied from 6.8 hours to 35 hours. The pharmacokinetics of everolimus were dose-proportional in that dose-normalized C(max) and area under the curve values were constant over the studied dose range. CONCLUSIONS: After implantation of everolimus-eluting self-expanding stents in the femoropopliteal arteries, systemic blood concentrations of everolimus are predictable and considerably lower than blood concentrations observed following safe oral administration of everolimus.

Effects of a ritonavir-containing regimen on the pharmacokinetics of sirolimus or everolimus in healthy adult subjects.

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.

Dose adjustment of venetoclax when co-administered with posaconazole: clinical drug-drug interaction predictions using a PBPK approach.

PURPOSE: Venetoclax, 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. METHODS: Two 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. RESULTS: The 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. CONCLUSIONS: The 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.

Expanding the Repertoire for "Large Small Molecules": Prodrug ABBV-167 Efficiently Converts to Venetoclax with Reduced Food Effect in Healthy Volunteers.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.