BRCA-Mutated Advanced Breast Cancer (BROCADE3) is a phase 3 study, evaluating veliparib in combination with carboplatin/paclitaxel with continuation as monotherapy if carboplatin/paclitaxel is discontinued in patients with germline BRCA1/2 mutation-associated, advanced human epidermal growth factor receptor 2-negative breast cancer. The objective of the current analysis was to characterize the veliparib exposure-response relationships for efficacy (progression-free survival [PFS]) and safety in this study. Exposure-efficacy analyses of PFS were conducted using Kaplan-Meier plots and cox proportional hazards (CPH) models using treatment alone or both treatment and exposure as time-dependent predictors to estimate the effect of veliparib in combination with carboplatin/paclitaxel and as monotherapy. The cox proportional hazards model with only treatment as the time-varying predictor estimated a statistically significant benefit of veliparib monotherapy compared to placebo monotherapy (hazard ratio, 0.49; 95%CI, 0.33-0.73) and a modest, non-statistically significant benefit (hazard ratio, 0.81; 95%CI, 0.62-1.05) of adding veliparib to carboplatin/paclitaxel. Inclusion of exposure as an additional time-varying predictor in the cox proportional hazards model indicated a flat exposure-response relationship between the veliparib exposure and PFS when veliparib was administered in combination with carboplatin/paclitaxel or as monotherapy. The exposure-safety analysis did not reveal any meaningful exposure-dependent trend in the incidence of adverse events of interest. These analyses support the dose regimen of veliparib (120 mg twice daily) in combination with carboplatin/paclitaxel and continuation of veliparib (300-400 mg twice daily) as monotherapy if carboplatin/paclitaxel were discontinued before disease progression in this patient population. This study is registered with ClinicalTrials.gov with a registration ID: NCT02163694.

BACKGROUND:Acute myeloid leukemia (AML) is a heterogenous malignancy driven by genetic and epigenetic factors. Inhibition of bromodomain and extraterminal (BET) proteins, epigenetic readers that play pivotal roles in the regulation of genes relevant to cancer pathogenesis, constitutes a novel AML treatment approach.METHODS:In this first-in-human study of the pan-BET inhibitor mivebresib as monotherapy (MIV-mono) or in combination with venetoclax (MIV-Ven), the safety profile, efficacy, and pharmacodynamics of mivebresib were determined in patients with relapsed/refractory AML (ClinicalTrials.gov identifier NCT02391480). Mivebresib was administered at 3 monotherapy dose levels (1.5, 2.0, or 2.5 mg) or in combination with venetoclax (400 or 800 mg).RESULTS:Forty-four patients started treatment: of 19 who started MIV-mono, 5 went on to receive MIV-Ven combination therapy after disease progression and a washout period. Twenty-five patients started MIV-Ven, resulting in a total of 30 patients treated with the combination. The most common mivebresib-related treatment-emergent adverse events were dysgeusia (74%), decreased appetite (42%), and diarrhea (42%) in the MIV-mono group and decreased appetite (44%), vomiting (44%), and nausea (40%) in the MIV-Ven group. Serious adverse events occurred in 14 patients (74%) who received MIV-mono and in 22 patients (88%) who received MIV-Ven. In the MIV-mono group, responses were complete remission with incomplete blood count recovery in 1 patient and resistant disease in 15 patients. In the MIV-Ven group, responses were complete remission in 2 patients, partial remission in 2 patients, morphologic leukemia-free state in 2 patients, resistant disease in 12 patients, and aplasia in 1 patient. The pharmacodynamic effects of mivebresib were proportional to dose and drug exposure.CONCLUSIONS:Mivebresib was tolerated and showed antileukemic effects as monotherapy and in combination with venetoclax in patients with relapsed/refractory AML.LAY SUMMARY:Mivebresib is a novel drug that influences the way cancer cells read genetic information. Mivebresib was tested together with venetoclax in patients with acute myeloid leukemia after standard medicines failed and the disease returned, or when standard medicine was unavailable. Adverse effects were described for different drug doses, and the dose that is tolerable was determined. In some patients, their leukemia improved for some time. More studies are necessary to determine whether mivebresib can be used to treat acute myeloid leukemia.

Veliparib (ABT-888) is a poly(ADP-ribose) polymerase inhibitor in development for the treatment of high-grade ovarian cancer or BRCA-mutated breast cancer in combination with carboplatin and paclitaxel. The population pharmacokinetics of veliparib were characterized using combined data from 1470 adult subjects with ovarian cancer, breast cancer, or other solid tumors enrolled in 6 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies of veliparib oral doses of 10 to 400 mg twice daily as monotherapy or in combination with chemotherapy. A 1-compartment model with linear clearance and first-order absorption best characterized veliparib pharmacokinetics. The predicted apparent oral clearance (CL/F) and volume of distribution (Vc /F) were 479 L/day and 152 L, respectively. The significant covariates in the final model included albumin, creatinine clearance, strong inhibitors of cytochrome P450 (CYP) 2D6, and sex on CL/F and albumin, body weight, and sex on Vc /F. Mild and moderate renal impairment increased veliparib median (95%CI) steady-state AUC (AUCss ) by 27.3% (23.7%-30.9%) and 65.4% (56.0%-75.5%), respectively, compared with normal renal function. Male subjects had 16.5% (7.53%-23.9%) lower AUCss compared with female subjects and coadministration with strong CYP2D6 inhibitors increased AUCss by 13.0% (6.11%-20.8%). Race, age, region, cancer type, or enzyme (CYP3A4, CYP2C19) or transporter (P-glycoprotein, multidrug and toxin extrusion protein 1/2, organic cation transporter 2) inhibiting/inducing comedications were not found to significantly impact veliparib pharmacokinetics. Other than baseline creatinine clearance and hence renal impairment effect on veliparib clearance, no other covariates had a clinically meaningful effect on veliparib exposure warranting dose adjustment.

Background: The bromodomain and extra terminal (BET) family of proteins bind acetylated histone tails, leading to the regulation of oncogenic target genes. Mivebresib (ABBV-075; MIV) is a pan-BET inhibitor that has demonstrated antitumor activity in vitro and in xenograft models of acute myeloid leukemia (AML). This phase 1, first-in-human, 2-part study (NCT02391480) assessed the safety and pharmacokinetics (PK) of MIV at various monotherapy (MIV-mono) or combination dosing schedules with venetoclax (MIV-VEN). Here we report PK and pharmacodynamic (PD) data in correlation to biological activity in patients with relapsed/refractory AML. Methods: Gene expression analysis was performed on RNA extracted from whole blood samples collected at multiple time points (pre-and post-MIV-mono treatment). mRNA expression was analyzed from total RNA and sequenced on HiSeq 3000 (Illumina, San Diego, CA). Soluble cytokine modulation was evaluated in serum samples (pre- and post-MIV-mono treatment) on Myriad Rules-Based Medicine's ExplorerMAP® Panel (145 analytes; Myriad RBM, Austin, TX). Cytogenetic analysis was performed at each site using institutional guidelines. Molecular profiling was performed at the site and by AbbVie using targeted next-generation sequencing (myeloid-specific panel). PK sampling was done on cycle 1 day 1 (C1D1), C1D8 and C2D1. PK analyses were completed using non-compartmental analysis methods. A linear regression analysis was performed to determine association between drug exposure and percentage change in gene modulation from baseline at 6 hours on C1D1. Biologic activity was defined as measurable reduction in bone marrow (BM) blasts from baseline. Results: As of Jan 2019, 44 patients (median age: 68 y [range, 29-84]; 35 patients >2 prior therapies) were enrolled: 19 in MIV-mono (5 of whom switched to MIV-VEN) and 25 who began treatment in MIV-VEN cohorts. MIV (1-2.5 mg) exposures were dose proportional and MIV was rapidly absorbed with a Tmax of 2-6 hours and terminal half-life of ~15-20 hours. Concomitant administration of VEN did not show any clinically significant effect on MIV plasma PK at steady state. At 6 hours post-MIV-mono treatment, a significant correlation was observed between drug exposure and PD biomarker modulation, with a dose-dependent gene expression increase in DCXR and HEXIM1 and decrease in CD93 (p<0.05). MIV-mono treatment also inhibited BCL-2,Myc, and VEGF gene expression and induced the expression of the pro-apoptotic genes BIM and PUMA following 6 hours of MIV-mono dosing. In patients treated with MIV-mono, measurable reduction in BM blast counts was observed in 7/19 (37%) patients (Figure): complete remission (CR) with incomplete blood count recovery (n=1), ≥50% blast reduction (n=4), modest blast reduction of <50% (n=3). In patients treated with MIV-VEN (n=30, including 5 patients who switched treatment), measurable reduction in BM blasts was observed in 15/30 (50%) patients (Figure): ≥50% blast reduction (n=10), including CR (n=2), partial remission (n=2), morphologic leukemia-free state (MLFS; n=1), and modest blast reduction of <50% (n=5). Median duration of response for all treated patients was 29 days (range, 11-581). Median duration (range) of response for MIV-mono, MIV-VEN, and switched treatment was 28.5 (11, 230), 29.0 (17, 145), and 31 (28, 581) days, respectively. The majority of patients (30/44; 68%) were classified as adverse risk per ELN 2017 criteria. At baseline, 6/19 (32%) MIV-mono and 17/30 (57%) MIV-VEN patients had mutations in signaling genes; FLT3-ITD/TKD were the most commonly mutated in MIV-VEN population (10/17, 59%). In the MIV-VEN group, 4/10 (40%) patients with FLT3-ITD/TKD mutations and 4/6 (67%) patients with PTPN11 mutations had reduction in BM blasts following treatment. At baseline, 12/30 (40%) patients had mutations in either SF3B1/U2AF1 or PTPN11; 8 (67%) of these patients had reduction in BM blasts, including 1 CR and 1 MLFS. Conclusions: MIV exposure was dose proportional and a significant correlation was identified between multiple biomarkers (HEXIM1, DCXR, CD93 gene modulation) and drug exposure at 6 hours post-MIV treatment. MIV treatment inhibited BCL-2, VEGF and Myc gene expression, while inducing expression of pro-apoptotic genes. Biologic activity was observed particularly in patients treated with MIV-VEN who had SF3B1/U2AF1 or PTPN11 mutations. Disclosures Borthakur: Arvinas: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cantargia AB: Research Funding; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Eisai: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Strategia Therapeutics: Research Funding; Polaris: Research Funding; Merck: Research Funding; Janssen: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; PTC Therapeutics: Consultancy; Incyte: Research Funding; GSK: Research Funding. Odenike:Agios: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; NS Pharma: Research Funding; Oncotherapy: Research Funding; Astra Zeneca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI/Baxalta: Research Funding; Astex Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Research Funding. Aldoss:Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria; AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Rizzieri:AbbVie: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Kite Pharma: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy; TEVA: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Amgen: Consultancy; Jazz Pharmaceuticals: Speakers Bureau; Millennium: Speakers Bureau. Prebet:Boehringer Ingelheim: Research Funding; pfizer: Honoraria; Tetraphase: Consultancy; Genentech: Consultancy; novartis: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria; novartis: Honoraria; novartis: Honoraria; Agios: Consultancy, Research Funding; pfizer: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; novartis: Honoraria; Boehringer Ingelheim: Research Funding; pfizer: Honoraria; pfizer: Honoraria; pfizer: Honoraria. Modi:AbbVie: Employment, Other: Stock/stock options. Joshi:AbbVie: Employment, Other: Stock/stock options. Hu:AbbVie: Employment, Other: Stock/stock options. Sun:AbbVie: Employment, Other: Stock/stock options. Wolff:AbbVie Inc: Employment, Other: Stock/stock options. Jonas:AbbVie, Amgen, GlycoMimetics: Other: Travel expenses; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding.

Acetylation is the major metabolic pathway of isoniazid (INH) mediated by N-acetyltransferases (NATs). Previous reports suggest that slow acetylators have higher risks of INH hepatotoxicity than rapid acetylators, but the detailed mechanisms remain elusive. The current study used Nat1/2(-/-) mice to mimic NAT slow metabolizers and to investigate INH metabolism in the liver. We found that INH acetylation is abolished in the liver of Nat1/2(-/-) mice, suggesting that INH acetylation is fully dependent on NAT1/2. In addition to the acetylation pathway, INH can be hydrolyzed to form hydrazine (Hz) and isonicotinic acid (INA). We found that INA level was not altered in the liver of Nat1/2(-/-) mice, indicating that deficiency of NAT1/2 has no effect on INH hydrolysis. Because INH acetylation was abolished and INH hydrolysis was not altered in Nat1/2(-/-) mice, we expected an extremely high level of INH in the liver. However, we only observed a modest accumulation of INH in the liver of Nat1/2(-/-) mice, suggesting that there are alternative pathways in INH metabolism in NAT1/2 deficient condition. Our further studies revealed that the conjugated metabolites of INH with endobiotics, including fatty acids and vitamin B6, were significantly increased in the liver of Nat1/2(-/-) mice. In summary, this study illustrated that deficiency of NAT1/2 decreases INH acetylation, but increases the interactions of INH with endobiotics in the liver. These findings can be used to guide future studies on the mechanisms of INH hepatotoxicity in NAT slow metabolizers.

Purpose: Mycophenolate Mofetil (MMF) is an immunosuppressive prodrug used as a prophylactic agent for graft rejection in solid organ and hematopoietic stem cell transplant patients. It undergoes immediate hydrolysis to the active form mycophenolic acid (MPA). The drug exhibits a large pharmacokinetic variability. There is poor correlation between trough concentration and MPA exposure measured as area under the plasma concentration -time curve (AUC). Our objective is to understand the physiological factors that influence the mycophenolic acid exposure using a validated physiologically based pharmacokinetic (PBPK) model in order to optimize therapy in transplant patients. Methods: Simcyp Simulator V15 was used to perform PBPK analysis. Physicochemical properties for mycophenolic acid were obtained from literature and a model was build and validated across doses of 500–1500 mg IV and oral of MMF in population cohorts of healthy volunteers, Chinese healthy volunteers and renal impairment. Pharmacokinetic parameters like Cmax, Tmax, AUC and Clearance were assessed and compared with the observed data. A full PBPK model was considered using an Advanced Dissolution Absorption Model (ADAM) to build the model. Parameter estimation using non-linear mixed effects was used to optimize tissue partitioning. The simulated clinical trials was carried out in the 100 virtual subjects from population groups of Simcyp’s platform: i) healthy volunteers, ii) renal impairment with GFR values between 30–60 iii) renal impairment with GFR below 30. Intrinsic clearance for each of the UGT enzymes was extrapolated from recombinant UGT data as reported by Picard et al using rUGT scalar. Results: The developed mechanistic models adequately described the pharmacokinetics mycophenolic acid after IV and oral doses in healthy volunteers, Chinese healthy volunteers and patients with varying degree of renal impairment. The predicted pharmacokinetic parameters for all the model naive data were within 1. 5 fold of the observed data. Conclusions: The top down bottom up PBPK-based approach showed a good correlation with the literature related to MPA pharmacokinetic parameters. This model has the potential to predict pharmacokinetics in other solid organ transplant recipients and thereby individualize MMF dosing. Dr. Sibylle Neuhoff.FigureFigureFigureReferences: 1. Picard N, Ratanasavanh D, Premaud A, Le Meur Y, Marquet P. Identification of the UDP‐glucuronosyltransferase isoforms involved in mycophenolic acid phase II metabolism. Drug Metab Dispos 2005;33:139–146. 2. Bullingham R, Monroe S, Nicholls A, Hale M. Pharmacokinetics and bioavailability of mycophenolate mofetil in healthy subjects after single-dose oral and intravenous administration. J Clin Pharmacol. 1996;36:315–324.

ABSTRACT Invasive fungal infections (IFIs) are common among lung transplant recipients (LTRs). Posaconazole is an important antifungal agent for both prophylaxis and treatment of IFIs; however, detailed pharmacokinetic data are limited among LTRs, particularly those with cystic fibrosis (CF). Our objective was to conduct a pharmacokinetic study of posaconazole oral suspension among LTRs, with particular attention to patients with CF. We enrolled 20 LTRs, 7 with CF and 13 with other underlying lung diseases. Average daily doses in CF and non-CF patients were 829 and 862 mg, respectively. After ≥5 days of treatment, only 4 patients had average plasma concentrations of >0.7 μg/ml. Average steady-state plasma concentrations were 61% lower in CF patients (0.233 μg/ml) than in non-CF LTRs (0.594 μg/ml; P = 0.03). The average dose-normalized plasma area-under-the-curve (AUC) values were also lower in CF (0.007 h·μg/ml) than in non-CF LTRs (0.02 h·μg/ml; P = 0.02). The weight-normalized apparent oral clearance values were 2.51 and 0.74 liters/h/kg among CF and non-CF LTRs, respectively ( P = 0.005). Despite significant interpatient variability, plasma trough concentrations were strongly correlated with posaconazole AUC across all LTRs ( r 2 = 0.95, P < 0.0001). Taken together, our study highlights a critical need to incorporate new formulations of posaconazole into prophylaxis and treatment strategies for LTRs, particularly those with CF. Future pharmacokinetic studies of both tablet and intravenous formulations must consider LTR-specific factors and incorporate a therapeutic drug monitoring plan in this patient population.

Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used increasingly for graft-versus-host disease (GVHD) prophylaxis. Empiric fixed-dose-escalation strategies in pediatric hematopoietic cell transplantation (HCT) recipients have failed to achieve target MPA exposure. We evaluated the safety and feasibility of a pharmacokinetics-based dosing approach using a novel continuous infusion (CI) method of administration of MMF in pediatric HCT recipients. All patients received a myeloablative conditioning with cyclosporine A and MMF for GVHD prophylaxis. MMF was initiated on day 0 at a dose of 15 mg/kg every 8 hours. Based on steady-state pharmacokinetics, MMF was converted to CI to target a total MPA AUC(0-24) of 40 to 80 μg·hour/mL. The MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7 to 3.3 μg/mL. During the CI schedule, MPA AUC(0-24) was maintained at a mean of 40.1 μg·hour/mL (range, 20.6 to 63.8), and 17 of 19 patients (89%) achieved MPA Css within target of 1.7 to 3.3 μg/mL. Eighteen of 19 patients (95%) achieved neutrophil engraftment at a median of 13 days (range, 8 to 41) post-transplant and platelet engraftment at 39 days (range, 17 to 298) days post-transplant. Six of 18 assessable patients (33%) developed stages II to IV acute GVHD and 2 of 15 (13%) developed chronic GVHD. The MMF dose was reduced in 9 patients due to gastrointestinal symptoms (n = 6), low blood counts (n = 4), and viral infection (n = 3). Five patients with acute lymphoblastic leukemia relapsed, of whom 4 have died. Fifteen of 19 patients are alive with a median follow-up of 2.4 years (range, .4 to 4.9), with 3-year event-free and overall survival rates of 68% and 79%, respectively. In this pilot study of pharmacokinetically directed MMF dosing, we observed no toxic deaths, excellent engraftment, and low rates of grades III to IV acute and chronic GVHD. We found significantly lower half-life and higher drug clearance in pediatric HCT recipients compared with stable pediatric renal transplant patients or adult transplant patients. This regimen deserves further validation in a larger cohort of pediatric patients undergoing myeloablative transplantation.

There are limited data available on the bioequivalence of generic and brand-name tacrolimus in pediatric and heart transplant patients. We characterized changes in 12-hour trough concentrations and clinical outcomes after transition from brand to generic tacrolimus in pediatric thoracic organ transplant recipients. Patients with a pharmacy-confirmed date of switch between generic and brand tacrolimus were identified, as well as a matched control group that did not switch for comparison. We identified 18 patients with a confirmed date of switch, and in 12 patients that remained on the same dose, trough concentrations were 14% less than when they were on brand (p = 0.037). The average change was -1.15 ± 1.76 ng/mL (p = 0.045). The control group did not experience a change in trough concentration and was different than the switched group (p = 0.005). There were no differences in dosage changes or kidney or liver function. In the year after switch, 24% of patients who were switched to generic experienced a rejection event vs. 18% in the patients on brand. We suggest a strategy of monitoring around the time of transition, and education of the patient/family to notify the care team when changes from brand to generic or between generics occur.