Characterization of Pharmacokinetics, Biotransformation and Elimination of Pomotrelvir Orally Administered in Healthy Male Adults Using Two [14C]-Labeled Microtracers with Separate Labeling Positions.

Pomotrelvir is an orally bioavailable, target antiviral inhibitor of the main protease (Mpro) of coronaviruses, including severe acute respiratory syndrome coronavirus 2, the etiological agent of Coronavirus Disease 2019. The pharmacokinetics, metabolism and elimination of two [14C]-labeled microtracers of 5 µCi/700 mg pomotrelvir with separate labeling positions (isotopomers), [lactam carbonyl-14C-pomotelvir] and [benzene ring-U-14C-pomotrelvir], following a single oral dose in healthy adult males was evaluated in two separate cohorts. Pomotrelvir was rapidly absorbed and eliminated primarily through metabolism and subsequently excreted via urine and feces. There were no differences in pomotrelvir pharmacokinetics between the two cohorts. The mean total radioactive dose recovered was 93.8% (n = 8) in the lactam cohort (58% in urine and 36% in feces) and 94.2% (n = 8) in the benzene cohort (75% in urine and 19% in feces), with ≥80% of [14C] recovered within 96 hours after dosing. About 5% and 3% of the intact pomotrelvir was recovered in feces and urine, respectively. Eleven major metabolites were detected and characterized using liquid chromatography-accelerator mass spectrometry and liquid chromatography tandem mass spectrometry methods, with three and six different metabolites elucidated in the samples collected from lactam and benzene cohorts, respectively, and two metabolites observed in both cohorts. The major metabolism pathway of pomotrelvir is through hydrolysis of its peptide bonds followed by phase II conjugations. These results support that the application of two radiolabeled isotopomers provided a comprehensive metabolite profiling analysis and was a successful approach in identifying the major disposition pathways of pomotrelvir that has complex routes of metabolism. SIGNIFICANCE STATEMENT: An unconventional approach using two differentially labeled [14C] microtracers, [lactam carbonyl-14C-pomotrelvir] and [benzene ring-U-14C-pomotrelvir] evaluated the mass balance of orally administered pomotrelvir in healthy adult males in two separate cohorts. The radioactive dose recovered in excreta was about 94% for both cohorts. While the two isotopomers of the radiolabeled-pomotrelvir showed no major differences in pharmacokinetics overall, they allowed for differential detection of their radiolabeled metabolites and appropriate characterization of their plasma exposure and excretion in urine and feces.

A population pharmacokinetic-pharmacodynamic model of navtemadlin, its glucuronide metabolite (M1) and serum macrophage inhibitory cykokine-1 (MIC-1).

Navtemadlin is a potent, selective, orally available inhibitor of murine double minute 2 that restores p53 activity to induce apoptosis in TP53 wild-type malignancies. Using richly sampled pharmacokinetic (PK) and pharmacodynamic (PD) data from healthy volunteers, a population PK/PD model was developed.A population PK (PPK) model described the PK characteristics of navtemadlin and its major metabolite acyl glucuronide (M1) and quantified enterohepatic recirculation (EHR). Post hoc individual PK parameters from this model were coupled with PD data for serum macrophage inhibitory cytokine-1 (MIC-1, GDF15), a cytokine biomarker of p53 activation, to construct a population PK/PD model that described plasma concentration-driven MIC-1 excursions and enabled simulation of the extent and duration of navtemadlin PD effects.The median apparent clearance (CL/F) and apparent central volume (V2/F) of navtemadlin were 36.4 L/hr and 159 L. The typical maximum stimulatory effect (Smax) was close to the median maximum MIC-1 ratio to baseline of 7.29 in observed data.Simulation revealed a dose-dependent increase of MIC-1 with steady state attained in approximately 7 days, in a 7-day-on/21-day-off dose regimen. Elevated MIC-1 concentrations persist through 17-19 days, leaving about 9-11 PD-free days in a 28-day cycle.

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.

BACKGROUND: New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. METHODS: We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. RESULTS: The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. CONCLUSIONS: Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).

Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial.

BACKGROUND: Ilorasertib (ABT-348) inhibits Aurora and VEGF receptor (VEGFR) kinases. Patients with advanced solid tumours participated in a phase 1 dose-escalation trial to profile the safety, tolerability, and pharmacokinetics of ilorasertib. METHODS: Ilorasertib monotherapy was administered at 10-180 mg orally once daily (Arm I, n = 23), 40-340 mg orally twice daily (Arm II, n = 28), or 8-32 mg intravenously once daily (Arm III, n = 7), on days 1, 8, and 15 of each 28-day cycle. RESULTS: Dose-limiting toxicities were predominantly related to VEGFR inhibition. The most frequent treatment-emergent adverse events ( > 30%) were: fatigue (48%), anorexia (34%), and hypertension (34%). Pharmacodynamic markers suggested that ilorasertib engaged VEGFR2 and Aurora B kinase, with the VEGFR2 effects reached at lower doses and exposures than Aurora inhibition effects. In Arm II, one basal cell carcinoma patient (40 mg twice daily (BID)) and one patient with adenocarcinoma of unknown primary site (230 mg BID) had partial responses. CONCLUSIONS: In patients with advanced solid tumours, ilorasertib treatment resulted in evidence of engagement of the intended targets and antitumour activity, but with maximum inhibition of VEGFR family kinases occurring at lower exposures than typically required for inhibition of Aurora B in tissue. CLINICAL TRIAL REGISTRATION: NCT01110486.

Metabolism and Disposition of a Novel B-Cell Lymphoma-2 Inhibitor Venetoclax in Humans and Characterization of Its Unusual Metabolites.

Venetoclax (ABT-199), a B-cell lymphoma-2 (Bcl-2) protein inhibitor, is currently in clinical development for the treatment of hematologic malignancies. We characterized the absorption, metabolism, and excretion of venetoclax in humans. After a single oral dose of [14C]venetoclax to healthy volunteers, the recovery of total radioactive dose was 100%, with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0.1%). The extent of absorption was estimated to be at least 65%. Venetoclax was primarily cleared by hepatic metabolism (∼66% of the administered dose). ∼33% of the administered dose was recovered as the parent drug and its nitro reduction metabolite M30 [2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((3-amino-4-(((tetrahydro-2H-pyran-4-yl)methyl)amino)phenyl)sulfonyl)-4-(4-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzamide] (13%) in feces. Biotransformation of venetoclax in humans primarily involves enzymatic oxidation on the dimethyl cyclohexenyl moiety, followed by sulfation and/or nitro reduction. Nitro reduction metabolites were likely formed by gut bacteria. Unchanged venetoclax was the major drug-related material in circulation, representing 72.8% of total plasma radioactivity. M27 (oxidation at the 6 position of cyclohexenyl ring followed by cyclization at the α-carbon of piperazine ring; 4-[(10aR,11aS)-7-(4-chlorophenyl)-9,9-dimethyl-1,3,4,6,8,10,10a,11a-octahydropyrazino[2,1-b][1,3]benzoxazin-2-yl]-N-[3-nitro-4-(tetrahydropyran-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide) was identified as a major metabolite, representing 12% of total drug-related material. M27 was primarily formed by cytochrome P450 isoform 3A4 (CYP3A4). Steady-state plasma concentrations of M27 in human and preclinical species used for safety testing suggested that M27 is a disproportionate human metabolite. M27 is not expected to have clinically relevant on- or off-target pharmacologic activities.

Effect of ketoconazole, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax, a BCL-2 inhibitor, in patients with non-Hodgkin lymphoma.

AIMS: To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. METHODS: Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5-11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8. RESULTS: Eleven patients had evaluable pharmacokinetic data and were therefore included in the statistical analyses. Compared to administration of a single 50 mg dose of venetoclax alone, ketoconazole increased the venetoclax mean maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to infinity (AUC∞ ) by 2.3-fold (90% confidence interval [CI]: 2.0-2.7) and 6.4-fold (90% CI: 4.5-9.2; range: 2- to 12-fold), respectively. CONCLUSIONS: Coadministration of venetoclax with multiple doses of ketoconazole resulted in a significant increase of venetoclax exposures, strongly suggesting that CYP3A plays a major role in elimination of venetoclax in patients. These results suggest the need to avoid concomitant use with strong and moderate inhibitors or inducers of CYP3A during the venetoclax ramp-up phase in chronic lymphocytic leukaemia (CLL) patients. For patients who have completed the ramp-up phase, a modification in venetoclax dose for use with strong and moderate inhibitors or inducers of CYP3A is recommended.

Pharmacokinetics of intravenous telavancin in healthy subjects with varying degrees of renal impairment.

PURPOSE: We evaluated the effect of renal impairment (RI) on the pharmacokinetics of telavancin and hydroxypropylbetadex (excipient in the telavancin drug product). METHODS: Adults with normal, mild, moderate or severe RI or end-stage renal disease (ESRD) receiving haemodialysis were included in two open-label, phase I studies of single-dose telavancin at 7.5 mg/kg (study A, n = 29) or 10 mg/kg (study B, n = 43). Pharmacokinetic analysis of telavancin and hydroxypropylbetadex plasma concentration versus time was performed in these subjects. RESULTS: The results in studies A and B were similar: telavancin systemic exposure (area under the concentration-time curve from 0 to infinity [AUC0-∞]) increased with RI. Telavancin half-life (h, mean ± SD) increased in subjects with severe RI compared with subjects with normal renal function from 6.9 ± 0.6 in study A and 6.5 ± 0.9 in study B to 14.5 ± 1.3 and 11.8 ± 6.7, respectively. Conversely, clearance (ml/h/kg, mean ± SD) decreased in subjects with severe RI compared with subjects with normal renal function from 13.7 ± 2.1 in study A and 17.0 ± 3.2 in study B to 6.18 ± 0.63 and 6.5 ± 1.5, respectively. Systemic exposures for hydroxypropylbetadex also increased with severity of RI. CONCLUSIONS: Results from two independent phase 1 studies suggest that dose adjustment of telavancin is required in subjects with varying degrees of RI.

Population pharmacokinetics of telavancin in healthy subjects and patients with infections.

A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of ≥ 75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function.

Pharmacokinetics and Macrophage Inhibitory Cytokine-1 Pharmacodynamics of the Murine Double Minute 2 Inhibitor, Navtemadlin (KRT-232) in Fed and Fasted Healthy Subjects.

This single 60-mg dose, 4-period crossover study assessed the effect of food and formulation change on navtemadlin (KRT-232) pharmacokinetics (PK) and macrophage inhibitory cytokine-1 (MIC-1) pharmacodynamics. Healthy subjects (N = 30) were randomized to 3 treatment sequences, A: new tablet, fasted (reference, dosed twice); B: new tablet, 30 minutes after a high-fat meal (test 1); C: old tablet, fasted (test 2). PK/pharmacodynamic parameters were measured over 0 to 96 hours. Adverse events were mild without any discontinuations. No serious adverse events or deaths occurred. In treatment A, navtemadlin mean (coefficient of variation) maximum concentration (Cmax ) was 525 (66) ng/mL, at median time to maximum concentration (tmax ) of 2 hours. Mean (coefficient of variation) area under the plasma concentration-time curve from time 0 to time t (AUC0-t ) was 3392 (63.3) ng • h/mL, and arithmetic mean terminal half-life was 18.6 hours. Acyl glucuronide metabolite (M1)/navtemadlin AUC0-t ratio was 0.2, and urine excretion of navtemadlin was negligible. After a meal (B vs A), navtemadlin tmax was delayed by 1 hour. Geometric least squares means ratios (90%CI) for navtemadlin Cmax and AUC0-t were 102.7% (87.4-120.6) and 81.4% (76.2-86.9), respectively. Old vs new tablet fasted formulations (C vs A) had geometric least squares means ratios (90%CI) of 78.4% (72.0-85.3) for Cmax and 85.9% (80.5-91.7) for AUC0-t . MIC-1 Cmax and AUC were comparable across groups; tmax was delayed relative to navtemadlin tmax by ≈8 hours. Navtemadlin AUC0-t and MIC-1 AUC0-t correlated significantly. In conclusion, navtemadlin can be administered safely with or without food; the new formulation does not affect navtemadlin PK. The 60-mg navtemadlin dose elicited a reproducible and robust MIC-1 response that correlated well with navtemadlin exposure, indicating that murine double minute 2 target engagement leads to p53 activation.

Phase I Dose-Escalation and -Expansion Study of Telisotuzumab (ABT-700), an Anti-c-Met Antibody, in Patients with Advanced Solid Tumors.

This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5-25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for MET amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, n = 15; dose expansion, n = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia (n = 9, 20.0%) and fatigue (n = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with MET-amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors (n = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with MET-amplified advanced solid tumors.

First-in-Human Phase I Study of ABBV-838, an Antibody-Drug Conjugate Targeting SLAMF7/CS1 in Patients with Relapsed and Refractory Multiple Myeloma.

PURPOSE: ABBV-838 is an antibody-drug conjugate targeting a unique epitope of CD2 subset 1, a cell-surface glycoprotein expressed on multiple myeloma cells. This phase I/Ib first-in-human, dose-escalation study (trial registration ID: NCT02462525) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-838 in patients with relapsed and refractory multiple myeloma (RRMM). PATIENTS AND METHODS: Eligible patients (≥18 years) received ABBV-838 (3+3 design) intravenously starting from 0.6 mg/kg up to 6.0 mg/kg for 3-week dosing intervals (Q3W). Patients could continue ABBV-838 for up to 24 months. Assessment of alternate dosing intervals (Q1W and Q2W) was conducted in parallel. RESULTS: As of March 2017, 75 patients received at least one dose of ABBV-838. The most common any-grade treatment-emergent adverse events (TEAE) were neutropenia and anemia (28.0% each), fatigue (26.7%), and nausea (25.3%). Grade 3/4/5 TEAEs were reported in 73.3% of patients across all treatment groups; most common were neutropenia (20.0%), anemia (18.7%), and leukopenia (13.3%). Grade 3/4/5 ABBV-838-related TEAEs were reported by 40.0% of patients across all treatment groups. Overall, 4.0% of patients experienced TEAEs leading to death, none ABBV-838 related. The MTD was not reached; the selected recommended dose for the expansion cohort was 5.0 mg/kg Q3W. Pharmacokinetic analysis showed that exposure was approximately dose proportional. The overall response rate was 10.7%; very good partial responses and partial responses were achieved by 2 (2.7%) and 6 (8.0%) patients, respectively. CONCLUSIONS: These results demonstrate that ABBV-838 is safe and well-tolerated in patients with RRMM with a very limited efficacy.

Lack of pharmacokinetic drug interactions following concomitant administration of telavancin with aztreonam or piperacillin/tazobactam in healthy participants.

This randomized crossover study in healthy participants assessed pharmacokinetic interactions between telavancin, aztreonam, and piperacillin/tazobactam. Part 1: 11 participants received telavancin 10 mg/kg, aztreonam 2 g, or a combination of telavancin 10 mg/kg+aztreonam 2 g intravenously on 3 separate days. Part 2: 12 participants received telavancin 10 mg/kg, piperacillin/tazobactam 4.5 g, or a combination of telavancin 10 mg/kg+piperacillin/tazobactam 4.5 g intravenously on 3 separate days. Blood and urine drug concentrations were measured up to 48 hours posttreatment. Drug interactions were assessed by equivalence analysis of noncompartmental pharmacokinetic parameters, focusing on area under plasma concentration-time curves (AUC), log transformed; if the antilog of the 90% confidence intervals (CIs) for the mean log AUC difference was within equivalence bounds (0.70, 1.43), the effect of coadministration on the pharmacokinetics of the respective drug was deemed not clinically significant. Plasma concentration-time curves for all treatment pairs were nearly superimposable with comparable values for pharmacokinetic parameter estimates. In equivalence analyses, 90% CI for the mean difference in log AUC in each comparison fell within the predefined clinical equivalence limits and bioequivalence limits (0.80, 1.25). Administration of aztreonam or piperacillin/tazobactam with telavancin had no clinically significant effect on the pharmacokinetic disposition of any of these drugs.

Multiple-dose pharmacokinetics of intravenous telavancin in healthy male and female subjects.

OBJECTIVES: The aim of this study was to assess the steady-state pharmacokinetic parameters of telavancin, an investigational bactericidal lipoglycopeptide, after intravenous (iv) administration to healthy male and female subjects. PATIENTS AND METHODS: In a randomized, double-blind, parallel-group, gender-stratified, two-dose study, 79 adult subjects received three daily 60 min iv infusions of telavancin at 7.5 mg/kg (n = 40) or 15 mg/kg (n = 39). Blood and urine samples were collected for pharmacokinetic analyses at admission, on day 3 pre-infusion and up to 48 h after the start of the day 3 infusion for 73 subjects (45 males and 28 females). Pharmacokinetic parameters were estimated by non-compartmental analysis. RESULTS: Following the day 3 telavancin dose (7.5 or 15 mg/kg), dose-proportional increases in mean peak plasma concentrations (C(max), 88 versus 186 mg/L for low and high doses, respectively) and total systemic exposures (AUC(0-24), 599 versus 1282 mg.h/L for low and high doses, respectively) were observed. Trough concentrations at steady state were 6 mg/L at 7.5 mg/kg/day and 16 mg/L at 15 mg/kg/day. The elimination half-life was dose-independent; the mean +/- SD ranged from 6.0 +/- 0.6 to 7.5 +/- 1.3 h for low and high doses, respectively. Approximately two-thirds of the total telavancin dose was excreted unchanged in urine over 48 h. Pharmacokinetic parameters were similar in males and females. CONCLUSIONS: Telavancin displayed linear plasma pharmacokinetics over the dose range 7.5-15 mg/kg/day and was primarily cleared via urinary excretion. No gender-related differences in the pharmacokinetic disposition of telavancin were observed. These data further characterize the pharmacokinetic profile of telavancin, a once-daily therapy targeted for the treatment of serious Gram-positive infections.

Pharmacokinetics of subcutaneous recombinant methionyl human leptin administration in healthy subjects in the fed and fasting states: regulation by gender and adiposity.

BACKGROUND: Recombinant methionyl human leptin (r-metHuLeptin) has demonstrated efficacy in improving hormonal and metabolic parameters in leptin-deficient states, and it has been suggested that leptin replacement may reverse metabolic adaptations during weight loss interventions. The pharmacokinetics of subcutaneously administered r-metHuLeptin have been recently published, but whether pharmacokinetic parameters are altered by short-term fasting, adiposity and/or gender has not yet been evaluated. OBJECTIVE: The objective of this study was to characterize pharmacokinetic parameters following subcutaneous r-metHuLeptin administration at doses in the physiological to supra-physiological to pharmacological range in the fed state and during 3-day complete fasting in lean and obese subjects, including both men and women. METHODS: We analysed pharmacokinetic profiles in five lean men, five obese men and five lean women following subcutaneous administration of physiological (0.01 mg/kg), supra-physiological (0.1 mg/kg) and pharmacological (0.3 mg/kg) doses of r-metHuLeptin given once in the fed state and once daily during 3-day complete caloric deprivation (fasting). RESULTS: With r-metHuLeptin administration at 0.01 mg/kg, leptin concentrations ranged up to approximately 7 ng/mL in lean men, approximately 20 ng/mL in obese men and approximately 30 ng/mL in lean women in the fed state. There was a significant effect of 3-day fasting: it decreased baseline leptin concentrations, peak serum concentration (C(max)) and area under the serum concentration-time curve from time zero to infinity (AUC(infinity)) [all p < 0.0001] and increased clearance (p < 0.001), most prominently in lean men (p < 0.0001 across the groups). Administration of r-metHuLeptin at 0.1 mg/kg resulted in leptin concentrations up to approximately 70 ng/mL in lean men, approximately 100 ng/mL in obese men and approximately 150 ng/mL in lean women in the fed state. At this dose, there was a similar effect of fasting on the pharmacokinetic parameters as well as a decrease in the terminal-phase elimination half-life (p = 0.02), consistent with increased clearance, but the effect of fasting was less pronounced overall than with the 0.01 mg/kg dose. With r-metHuLeptin administration at 0.3 mg/kg, leptin concentrations ranged up to approximately 150 ng/mL in lean men, approximately 300 ng/mL in obese men and approximately 400 ng/mL in lean women in the fed state. At this dose, fasting increased clearance to a lesser degree (p = 0.046), mainly in lean men, suggesting that the fasting-induced increase in leptin clearance by the kidneys can plateau. Within each group, the subjects lost approximately 3-4 kg of bodyweight after 3 days of fasting (all p < 0.0001), but the amount and time course of weight loss did not differ according to the dose of r-metHuLeptin administered or the circulating leptin concentrations achieved. CONCLUSIONS: Short-term fasting in healthy individuals results in increased clearance of leptin; this contributes to hypoleptinaemia, which may serve as a signal to increase energy intake in the setting of caloric restriction. Obese individuals with greater energy stores at baseline have a blunted response to the fasting-induced increase in leptin clearance. Also, women have a differential response to fasting, with primarily decreased leptin production rather than increased clearance. These findings and the resulting formulas for calculating doses for r-metHuLeptin administration have important implications for future therapeutic use of r-metHuLeptin in conjunction with hypocaloric diets for the treatment of obesity.

Pharmacokinetics of recombinant methionyl human leptin after subcutaneous administration: variation of concentration-dependent parameters according to assay.

CONTEXT: Recombinant human leptin (r-metHuLeptin) has demonstrated efficacy in improving hormonal and metabolic parameters in leptin-deficient states, but pharmacokinetic parameters after sc administration have not yet been published. In addition, the effect of potential variability across different leptin assays on concentration-dependent pharmacokinetic parameters remains unknown. OBJECTIVE: The objective of the study was to characterize pharmacokinetic parameters after sc r-metHuLeptin administration using three commercially available leptin assays (Linco, Diagnostic Systems Laboratories, and Alpco). DESIGN, SETTING, PATIENTS, AND INTERVENTION: We analyzed pharmacokinetic profiles in five lean and five obese men after sc administration of physiological (0.01 mg/kg) and pharmacological (0.3 mg/kg) doses of r-metHuLeptin. MAIN OUTCOME MEASURES: Leptin pharmacokinetic parameters were measured. RESULTS: Measurement of leptin produced typical pharmacokinetic profiles in all assays with time to maximal concentration and half-life of approximately 3 h. Diagnostic Systems Laboratories consistently measured leptin higher than Linco, with Alpco measuring intermediate between or similar to Linco. There was high correlation among assays (R(2) ranging from 0.89 to 0.98, all P < 0.01). Concentration-dependent parameters such as maximal concentration, area under the curve, and clearance were significantly different among assays, whereas concentration-independent parameters such as time to maximal concentration and half-life were generally not different. CONCLUSIONS: We report novel data on leptin pharmacokinetic parameters after sc administration, which will be relevant for the future therapeutic use of r-metHuLeptin. Although commercially available assays demonstrated high correlation, they can provide substantially different measures of leptin levels. This demonstrates the importance of standardizing leptin assays for diagnosing patients with relative leptin deficiency, determining appropriate doses of r-metHuLeptin for administration, and monitoring response to therapy.

Pharmacokinetics of Venetoclax, a Novel BCL-2 Inhibitor, in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Non-Hodgkin Lymphoma.

Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics. Patients received a once-daily venetoclax dose of 20 to 1200 mg. Pharmacokinetic parameters were estimated using noncompartmental methods. Venetoclax peak exposures were achieved at 5 to 8 hours under low-fat conditions, and the mean terminal-phase elimination half-life ranged between 14.1 and 18.2 hours at different doses. Venetoclax steady-state exposures showed minimal accumulation and increased proportionally over the dose range of 300 to 900 mg. Low-fat and high-fat meals increased venetoclax exposures by approximately 4-fold relative to the fasting state. Moderate CYP3A inhibitors increased venetoclax exposures by 40% to 60%, whereas weak CYP3A inhibitors had no effect. A negligible amount of venetoclax was excreted in the urine. In summary, venetoclax exhibits a pharmacokinetic profile that is compatible with once-daily dosing with food regardless of fat content. Concomitant use of venetoclax with moderate CYP3A inhibitors should be avoided or venetoclax dose should be reduced during the venetoclax initiation and ramp-up phase in CLL patients. Renal excretion plays a minimal role in the elimination of venetoclax.

Evaluation of the Pharmacokinetic Interaction between Venetoclax, a Selective BCL-2 Inhibitor, and Warfarin in Healthy Volunteers.

BACKGROUND AND OBJECTIVE: Venetoclax is a selective, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. In vitro data indicated weak cytochrome P450 (CYP) 2C9 inhibition by venetoclax; however, it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. A Phase 1 study was conducted in healthy volunteers to evaluate the effect of venetoclax on warfarin pharmacokinetics. METHODS: Subjects received a single oral dose of 5 mg warfarin on day 1 of both periods 1 and 2, separated by a 14 days washout. On day 1 of period 2, subjects concomitantly received a single 400 mg oral dose of venetoclax. Blood samples for warfarin concentration determination were collected after each dose administration for up to 9 days. RESULTS: Modest increases of 18 to 28% were observed in the maximum observed plasma concentration (C max) and area under the curve from time zero to infinity (AUC∞) of both R- and S-warfarin. CONCLUSIONS: Due to the narrow therapeutic window of warfarin, it is recommended that the international normalized ratio (INR) be monitored closely in patients receiving venetoclax and warfarin. Since similar increases in exposure were observed for both enantiomers, even though CYP2C9 is only involved in the metabolism of the S-enantiomer, and the half-life of both enantiomers remained the same, the interaction does not appear to be mediated via CYP2C9.

Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia.

BACKGROUND: Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies. OBJECTIVE: The objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). METHODS: A total of 272 and 338 patients from four clinical studies were pooled for the exposure-efficacy and exposure-safety analyses, respectively. Demographics, baseline disease characteristics, and select co-medications were evaluated for their impact on efficacy (lymphocytes, tumor size, objective response [OR]) and safety (neutropenia and infection). RESULTS: Higher venetoclax concentrations led to a more rapid decrease in lymphocyte counts and tumor size, which translated into patients more rapidly achieving OR. The 17p deletion somatic mutation was not identified, in any of the analyses, to affect the responsiveness of patients to venetoclax. Model-based simulations of lymphocyte counts and tumor size estimated an OR rate (ORR) of 84.8 % (95 % confidence interval 81.5-88.0 %) at a venetoclax dosage of 400 mg daily, with minimal increase in ORR at higher doses. The safety analyses of the adverse events (grade 3 or higher) of neutropenia and infection indicated that higher average venetoclax concentrations were not associated with an increase in adverse events. CONCLUSIONS: The exposure-response analyses indicated that a venetoclax dosage regimen of 400 mg daily results in a high (>80 %) probability of achieving OR in R/R CLL/SLL patients, with minimal probability of increasing neutropenia or infection with higher exposures.

Management of Venetoclax-Posaconazole Interaction in Acute Myeloid Leukemia Patients: Evaluation of Dose Adjustments.

PURPOSE: 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. METHODS: 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. FINDINGS: 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. IMPLICATIONS: 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.

Discovery of N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor.

The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9-19-fold. Additional structure-activity relationship (SAR) efforts aimed both at increasing potency and improving pharmacokinetic properties led to the discovery of the clinical candidate 63 (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation.