Intrapulmonary pharmacokinetics of SPR719 following oral administration of SPR720 to healthy volunteers.

SPR720 is a phosphate ester prodrug that is converted rapidly to SPR719, the active moiety, which exhibits potent activity against clinically relevant mycobacterial species including complex (MAC) and . SPR720 is in clinical development for the treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD) due to MAC. This study evaluated the safety and the intrapulmonary pharmacokinetics of SPR719 in healthy volunteers.

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

Pomotrelvir is an orally bioavailable, target antiviral inhibitor of the main protease (M) of coronaviruses, including severe acute respiratory syndrome coronavirus 2, the etiological agent of Coronavirus Disease 2019. The pharmacokinetics, metabolism and elimination of two [C]-labeled microtracers of 5 Ci/700 mg pomotrelvir with separate labeling positions (isotopomers), [lactam carbonyl-C-pomotelvir] and [benzene ring-U-C-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.

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 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).

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.

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 amplification (FISH screening).

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.

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.

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.

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/m 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.

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.

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.

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.

Venetoclax does not prolong the QT interval in patients with hematological malignancies: an exposure-response analysis.

Purpose: Venetoclax (ABT-199/GDC-0199) is a selective first-in-class B cell lymphoma-2 inhibitor being developed for the treatment of hematological malignancies. The aim of this study was to determine the potential of venetoclax to prolong the corrected QT (QTc) interval and to evaluate the relationship between systemic venetoclax concentration and QTc interval.

Methods: The study population included 176 male and female patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 105) or non-Hodgkin's lymphoma (n = 71) enrolled in a phase 1 safety, pharmacokinetic, and efficacy study.

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.

Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis.

Venetoclax (ABT-199/GDC-0199) is a selective, potent, first-in-class BCL-2 inhibitor that restores apoptosis in cancer cells and has demonstrated clinical efficacy in a variety of hematological malignancies. The objective of this analysis was to characterize the population pharmacokinetics of venetoclax and identify demographic, pathophysiologic, and treatment factors that influence its pharmacokinetics. Plasma concentration samples from 505 subjects enrolled in 8 clinical studies were analyzed using non-linear mixed-effects modeling.

Effect of Low- and High-Fat Meals on the Pharmacokinetics of Venetoclax, a Selective First-in-Class BCL-2 Inhibitor.

Venetoclax is a selective, first-in-class, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in several hematological malignancies. Two studies evaluated the relative bioavailability of venetoclax in healthy subjects: (1) a bioequivalence study to compare the bioavailability of the film-coated tablet with that of an earlier uncoated tablet and (2) a food effect study to evaluate the effect of food on venetoclax pharmacokinetics. Both studies were open-label, single-dose, crossover studies.

Evaluation of Rifampin's Transporter Inhibitory and CYP3A Inductive Effects on the Pharmacokinetics of Venetoclax, a BCL-2 Inhibitor: Results of a Single- and Multiple-Dose Study.

Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. A single-dose and multiple-dose rifampin study was conducted to evaluate the effect of CYP3A induction and transporter inhibition on the pharmacokinetics of venetoclax. Subjects received a single dose of venetoclax 200 mg on day 1 of period 1 and days 1 and 14 of period 2, a single dose of rifampin 600 mg on day 1 of period 2, and rifampin 600 mg once daily on days 5 through 17 of period 2.

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.

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).

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.

Single-dose pharmacokinetics and tolerability of telavancin in elderly men and women.

Study Objective: To assess the safety and tolerability, and the effect of sex on the pharmacokinetic disposition, of a single intravenous dose of telavancin 10 mg/kg in elderly (> or = 65 yrs) subjects.

Design: Phase I, open-label, single-dose, sex-stratified study.

Setting: Clinical research unit.

Effect of Telavancin on the pharmacokinetics of the cytochrome P450 3A probe substrate midazolam: a randomized, double-blind, crossover study in healthy subjects.

Study Objective: To examine the effect of telavancin, a lipoglycopeptide antibiotic with potent gram-positive activity, on the pharmacokinetics of midazolam, a cytochrome P450 (CYP) 3A probe substrate. Design. Phase I, randomized, double-blind, placebo-controlled, crossover study.

Lack of effect of moderate hepatic impairment on the pharmacokinetics of telavancin.

Study Objective: To evaluate the pharmacokinetics of the lipoglycopeptide antibiotic, telavancin, in patients with moderate hepatic impairment compared with healthy controls.

Design: Phase I, open-label, single-dose, matched-control, pilot study.

Setting: Clinical research unit.

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.