Vijay Ivaturi

Isoniazid clearance is impaired among human immunodeficiency virus/tuberculosis patients with high levels of immune activation

AIMS Immune activation, which is characteristic of both tuberculosis (TB) and human immunodeficiency virus (HIV) infection, is associated with impaired drug metabolism. We tested the hypothesis that elevated levels of systemic immune activation among adults with HIV/TB initiating antiretroviral therapy (ART) would be associated with impaired clearance of isoniazid. METHODS We conducted a prospective observational study of isoniazid pharmacokinetics (PK) and systemic immune activation prior to and 1 month after ART initiation. Nonlinear mixed effects analysis was performed to measure the covariate effect of immune activation on isoniazid clearance in a model that also included N‐acetyltransferase‐2 (NAT‐2) genotype and interoccasional variability on clearance (thereby analyzing the PK data before and after ART initiation in a single model). RESULTS We enrolled 40 patients in the PK visit prior to ART, and 24 patients returned for the second visit a median of 33 days after initiating antiretroviral therapy. The isoniazid concentration data were best described by a two‐compartment model with first‐order elimination. After accounting for NAT‐2 genotype, increasing levels of CD38 and HLA‐DR expression on CD8+ T cells (CD38+DR+CD8+) were associated with decreasing isoniazid clearance. CONCLUSION HIV/TB patients with high levels of immune activation demonstrated impaired isoniazid clearance. Future efforts should determine the role of this relationship in clinical hepatotoxicity events.

Mechanistic Population Pharmacokinetics of Morphine in Neonates With Abstinence Syndrome After Oral Administration of Diluted Tincture of Opium.

Conducting and analyzing clinical trials in vulnerable neonates are extremely challenging. The aim of this analysis is to develop a morphine population pharmacokinetics (PK) model using data collected during a randomized control trial in neonates with abstinence syndrome (NAS). A 3‐compartment morphine structural PK model after intravenous (IV) administration from previously published work was utilized as prior, whereas an allometric scaling method with physiological consideration was used to extrapolate a PK profile from adults to pediatrics. The absorption rate constant and bioavailability were estimated in NAS after oral administration of diluted tincture of opium (DTO). Goodness‐of‐fit plots along with normalized prediction distribution error and bootstrap method were performed for model evaluation. We successfully extrapolated the PK profile from adults to pediatrics after IV administration. The estimated first‐order absorption rate constant and bioavailability were 0.751 hour−1 and 48.5%, respectively. Model evaluations showed that the model can accurately and precisely describe the observed data. The population pharmacokinetic model we derived for morphine after oral administration of DTO is reasonable and acceptable; therefore, it can be used to describe the PK and guide future studies. The integration of the previous population PK knowledge as prior information successfully overcomes the logistic and practical issue in vulnerable neonate population.

Efficacy and Safety of Intravenous Chlorothiazide versus Oral Metolazone in Patients with Acute Decompensated Heart Failure and Loop Diuretic Resistance.

To assess the efficacy and safety of intravenous (IV) chlorothiazide versus oral metolazone when added to loop diuretics in patients with acute decompensated heart failure (ADHF) and loop diuretic resistance.

Isoniazid clearance is impaired among HIV/tuberculosis patients with high levels of immune activation

AIMS Immune activation, which is characteristic of both tuberculosis (TB) and human immunodeficiency virus (HIV) infection, is associated with impaired drug metabolism. We tested the hypothesis that elevated levels of systemic immune activation among adults with HIV/TB initiating antiretroviral therapy (ART) would be associated with impaired clearance of isoniazid. METHODS We conducted a prospective observational study of isoniazid pharmacokinetics (PK) and systemic immune activation prior to and 1 month after ART initiation. Nonlinear mixed effects analysis was performed to measure the covariate effect of immune activation on isoniazid clearance in a model that also included N‐acetyltransferase‐2 (NAT‐2) genotype and interoccasional variability on clearance (thereby analyzing the PK data before and after ART initiation in a single model). RESULTS We enrolled 40 patients in the PK visit prior to ART, and 24 patients returned for the second visit a median of 33 days after initiating antiretroviral therapy. The isoniazid concentration data were best described by a two‐compartment model with first‐order elimination. After accounting for NAT‐2 genotype, increasing levels of CD38 and HLA‐DR expression on CD8+ T cells (CD38+DR+CD8+) were associated with decreasing isoniazid clearance. CONCLUSION HIV/TB patients with high levels of immune activation demonstrated impaired isoniazid clearance. Future efforts should determine the role of this relationship in clinical hepatotoxicity events.

Exposure–Response Analysis of Alvocidib (Flavopiridol) Treatment by Bolus or Hybrid Administration in Newly Diagnosed or Relapsed/Refractory Acute Leukemia Patients

Purpose: To elucidate any differences in the exposure–response of alvocidib (flavopiridol) given by 1-hour bolus or a hybrid schedule (30-minute bolus followed by a 4-hour infusion) using a flavopiridol/cytosine arabinoside/mitoxantrone sequential protocol (FLAM) in patients with acute leukemia. The hybrid schedule was devised to be pharmacologically superior in chronic leukemia based on unbound exposure. Experimental Design: Data from 129 patients in three FLAM studies were used for pharmacokinetic/pharmacodynamic modeling. Newly diagnosed (62%) or relapsed/refractory (38%) patients were treated by bolus (43%) or hybrid schedule (57%). Total and unbound flavopiridol concentrations were fit using nonlinear mixed-effect population pharmacokinetic methodologies. Exposure–response relationships using unbound flavopiridol AUC were explored using recursive partitioning. Results: Flavopiridol pharmacokinetic parameters were estimated using a two-compartment model. No pharmacokinetic covariates were identified. Flavopiridol fraction unbound was 10.9% and not different between schedules. Partitioning found no association between dosing schedule and clinical response. Clinical response was associated with AUC ≥ 780 h*ng/mL for newly diagnosed patients and AUC ≥ 1,690 h*ng/mL for relapsed/refractory patients. Higher exposures were not associated with increases in severe adverse events (≥ grade 3). Conclusions: Pharmacokinetic modeling showed no difference in flavopiridol plasma protein binding for bolus versus hybrid dosing. Further trials in newly diagnosed patients with acute leukemia should utilize the bolus FLAM regimen at the MTD of 50 mg/m2/day. Trials in relapsed/refractory patients should use the hybrid dosing schedule at the MTD (30/60 mg/m2/day) to achieve the higher exposures required for maximal efficacy in this population. Clin Cancer Res; 23(14); 3592–600. ©2017 AACR.

Parent‐Metabolite Pharmacokinetic Modeling and Pharmacodynamics of Veliparib (ABT‐888), a PARP Inhibitor, in Patients With BRCA 1/2–Mutated Cancer or PARP‐Sensitive Tumor Types

Veliparib (ABT‐888) is a novel oral poly‐ADP‐ribose polymerase (PARP) inhibitor that is being developed for the treatment of hematologic malignancies and solid tumors. Although the pharmacokinetics of veliparib have been studied in combination with cytotoxic agents, limited information exists regarding the pharmacokinetics (PK) of chronically dosed single‐agent veliparib in patients with either BRCA 1/2–mutated cancer or PARP‐sensitive tumors. The objectives of the current analysis were to characterize the population pharmacokinetics of veliparib and its primary, active metabolite, M8, and to evaluate the relationship between veliparib and M8 concentrations and poly‐ADP‐ribose (PAR) level observed in peripheral blood mononuclear cells (PBMCs). Seventy‐one subjects contributed with veliparib plasma concentrations, M8 plasma concentrations, and PAR levels in PBMCs. Veliparib and M8 concentrations were modeled simultaneously using a population PK approach. A 2‐compartment model with delayed first‐order absorption and the elimination parameterized as renal (CLR/F) and nonrenal clearance (CLNR/F) adequately described veliparib pharmacokinetics. The pharmacokinetics of the M8 metabolite was described with a 2‐compartment model. Creatinine clearance(CLCR) and lean body mass (LBM) were identified as significant predictors of veliparib CLR/F and central volume of distribution, respectively. For a typical subject (LBM, 48 kg; CLCR, 95 mL/min), total clearance (CLR/F + CLNR/F), and central and peripheral volume of distribution for veliparib were estimated as 17.3 L/h, 98.7 L, and 48.3 L, respectively. At least 50% inhibition of PAR levels in PBMCs was observed at dose levels ranging from 50 to 500 mg.

Abstract CT101: A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types

Introduction: The anti-PD-1 checkpoint inhibitor NIVO provides favorable safety and efficacy when administered at 3 mg/kg Q2W across multiple tumor types. Alternative dosing schedules would provide flexibility and offer benefits to patients and prescribers. A well-established understanding of NIVO clinical pharmacology, robust clinical data across multiple tumor types and well characterized, relatively flat E-R relationships for efficacy and safety support the use of model-based approaches to qualify other potential NIVO doses and schedules. Methods: The feasibility of extending the dosing interval of NIVO from Q2W to Q4W was investigated using a combination of quantitative clinical pharmacology analyses and safety assessments. The predicted benefit-risk profile of NIVO 480 mg Q4W relative to 3 mg/kg Q2W was assessed by the following analyses: (1) comparison of NIVO exposures produced by 3 mg/kg Q2W and 480 mg Q4W across tumor types; (2) evaluation of NIVO exposure margins for safety relative to the well-tolerated dose of 10 mg/kg Q2W; (3) comparison of predicted risk of experiencing adverse events (Gr3+ AEs, immune-mediated AEs) with 480 mg Q4W relative to 3 mg/kg Q2W across indications of melanoma, NSCLC, RCC, UC, HN and (4) comparison of predicted objective tumor response (OR) and overall survival with NIVO 480 mg Q4W relative to 3 mg/kg Q2W in patients with melanoma, NSCLC, and RCC. Results: Steady-state peak, time-averaged, and trough NIVO concentrations predicted with 480 mg Q4W were approximately 44% higher, 4% higher, and 18% lower, respectively, compared with 3 mg/kg Q2W. The aggregate of safety data accumulated for NIVO up to a dose level of 10 mg/kg Q2W in multiple tumor types provides a wide safety margin for the maximum concentration values expected with 480 mg Q4W. The steady-state exposures produced by 480 mg Q4W were lower than the corresponding exposures with 10 mg/kg Q2W, which has been shown to have acceptable safety and tolerability. The predicted probabilities of achieving an OR with NIVO 480 mg Q4W were similar to those with 3 mg/kg Q2W ( Conclusion: With a well-established understanding of NIVO clinical pharmacology, robust clinical data across multiple tumor types and well-characterized E-R relationships for efficacy and safety, the differences in exposures produced by a NIVO schedule of 480 mg Q4W relative to 3 mg/kg Q2W dosing schedule are not expected to result in clinically meaningful differences in the safety and efficacy of NIVO. The proposed 480 mg Q4W schedule has been incorporated into NIVO clinical trials (NCT02713867, NCT02714218) across multiple tumor types. Citation Format: Xiaochen Zhao, Vijay Ivaturi, Mathangi Gopalakrishnan, Jun Shen, Yan Feng, Paul Statkevich, Eric Richards, Michelle Rashford, Vicki Goodman, Joga Gobburu, Akintunde Bello, Amit Roy, Shruti Agrawal. A model-based exposure-response (E-R) assessment of a nivolumab (NIVO) 4-weekly (Q4W) dosing schedule across multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT101. doi:10.1158/1538-7445.AM2017-CT101

Observation of Patients Transitioned to an Oral Loop Diuretic Before Discharge and Risk of Readmission for Acute Decompensated Heart Failure

BACKGROUND Heart failure (HF) is associated with high 30-day readmission rates and places significant financial burden on the health care system. The aim of this study was to determine if the duration of observation on an oral loop diuretic before discharge is associated with a reduction in 30-day HF readmission in patients with acute decompensated HF (ADHF). METHODS AND RESULTS This was a retrospective study of adult patients admitted for ADHF at a large academic medical center. A total of 123 patients were included. Baseline characteristics were similar between groups. The primary outcome of 30-day HF readmission occurred in 11 of 61 patients (18%) observed on an oral loop diuretic for <24 hours and in 2 of 62 patients (3.2%) observed on an oral loop diuretic for ≥24 hours (P = .023). Readmissions for 60- and 90-day HF were also significantly lower in patients observed for ≥24 hours (P = .014 and P = .049, respectively). Associations became stronger after multivariate analysis (P < .001). Observation for <24 hours and previous admission within 30 days were independent predictors of 30-day HF readmission (P = .03). CONCLUSIONS Observation of patients on an oral loop diuretic for <24 hours was associated with significantly higher 30-day HF readmission. Therefore, observation on an oral loop diuretic for ≥24 hours before discharge in patients presenting with ADHF should be strongly considered.

Preservation of myocardial contractility during acute hypoxia with OMX-CV, a novel oxygen delivery biotherapeutic

The heart exhibits the highest basal oxygen (O2) consumption per tissue mass of any organ in the body and is uniquely dependent on aerobic metabolism to sustain contractile function. During acute hypoxic states, the body responds with a compensatory increase in cardiac output that further increases myocardial O2 demand, predisposing the heart to ischemic stress and myocardial dysfunction. Here, we test the utility of a novel engineered protein derived from the heme-based nitric oxide (NO)/oxygen (H-NOX) family of bacterial proteins as an O2 delivery biotherapeutic (Omniox-cardiovascular [OMX-CV]) for the hypoxic myocardium. Because of their unique binding characteristics, H-NOX–based variants effectively deliver O2 to hypoxic tissues, but not those at physiologic O2 tension. Additionally, H-NOX–based variants exhibit tunable binding that is specific for O2 with subphysiologic reactivity towards NO, circumventing a significant toxicity exhibited by hemoglobin (Hb)-based O2 carriers (HBOCs). Juvenile lambs were sedated, mechanically ventilated, and instrumented to measure cardiovascular parameters. Biventricular admittance catheters were inserted to perform pressure-volume (PV) analyses. Systemic hypoxia was induced by ventilation with 10% O2. Following 15 minutes of hypoxia, the lambs were treated with OMX-CV (200 mg/kg IV) or vehicle. Acute hypoxia induced significant increases in heart rate (HR), pulmonary blood flow (PBF), and pulmonary vascular resistance (PVR) (p < 0.05). At 1 hour, vehicle-treated lambs exhibited severe hypoxia and a significant decrease in biventricular contractile function. However, in OMX-CV–treated animals, myocardial oxygenation was improved without negatively impacting systemic or PVR, and both right ventricle (RV) and left ventricle (LV) contractile function were maintained at pre-hypoxic baseline levels. These data suggest that OMX-CV is a promising and safe O2 delivery biotherapeutic for the preservation of myocardial contractility in the setting of acute hypoxia.

Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure‐FLT3 Relationship

Sorafenib administered at the approved dose continuously is not tolerated long‐term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure‐response relationship in patients with AML. A one‐compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS‐like tyrosine kinase 3 (FLT3)‐ITD and extracellular signal‐regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax) model. Sorafenib could inhibit FLT3‐ITD activity by 100% with an IC50 of 69.3 ng/mL and ERK activity by 84% with an IC50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure‐response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3‐ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML.