This study investigates the impact of severe renal impairment on the pharmacokinetics of cabotegravir, an investigational HIV-1 integrase inhibitor. This was a phase I, open-label, parallel-group, multicenter study conducted in 8 participants with severe renal impairment (creatinine clearance <30 mL/min; no renal replacement therapy) and 8 healthy participants (creatinine clearance >90 mL/min; 2 women/group; 6 men/group) matched for sex, age (±10 years), and body mass index (±25%). Participants received a single 30-mg oral cabotegravir tablet to determine total and unbound plasma cabotegravir concentrations. Arithmetic and geometric least squares means were calculated, and cabotegravir noncompartmental pharmacokinetic parameters were compared using geometric least squares mean ratios with 90% confidence intervals. Safety was assessed throughout the study. Geometric least squares mean ratios (90% confidence intervals) were 0.97 (0.84-1.14) for area under the plasma concentration-time curve extrapolated to infinity, 1.01 (0.87-1.17) for maximum observed plasma concentration, 1.31 (0.84-2.03) for unbound cabotegravir 2 hours after dosing, and 1.51 (1.19-1.92) for unbound cabotegravir 24 hours after dosing. All adverse events were grade 1, except grade 3 lipase elevation in a participant with renal impairment. Severe renal impairment did not impact plasma cabotegravir exposure, and cabotegravir may be administered without dose adjustment in renal impairment among patients not receiving renal replacement.

Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression.

This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers.

Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC).

Altered pharmacokinetics of antibody drugs has been reported in advanced gastric cancer (AGC). We aim to evaluate bevacizumab pharmacokinetics in AGC from the Phase III trial (AVAGAST), and explore the influence of patient variables. Bevacizumab concentrations (Cp) were measured in plasma samples taken following disease progression from 162 patients (7.5 mg/kg every 3 weeks). Predicted Cp [median and 90% prediction interval] was simulated using the population pharmacokinetic model established for other cancers (PPK model) and compared to observed Cp. Bevacizumab clearance was estimated using NONMEM and compared between subgroups. Patient characteristics of AGC are similar to other cancers except for lower body weight despite higher percentage of males. Eighty-five percent of observed Cp was below the median predicted Cp and 38% below the lower boundary of the 90% prediction interval. Median bevacizumab clearance in AGC was 4.5 versus 3 mL/day/kg in other cancers. Bevacizumab clearance was significantly faster (p < 0.05) in patients without gastrectomy (n = 42) or lower albumin. Clearance appeared to be faster in patients with lower total protein, higher ECOG scores, more metastatic sites, and poorer response. No significant difference in bevacizumab concentrations and clearance was observed between Asian and Non-Asian patients. AGC patients exhibited significantly lower bevacizumab exposure due to an approximate 50% increase in clearance versus other cancers. Bevacizumab is cleared faster in patients without prior gastrectomy. No significant difference in bevacizumab pharmacokinetics was observed between Asian and Non-Asian patients. The underlying mechanism for faster bevacizumab clearance in AGC is unknown and warrants further research.

The aim of the present study was to evaluate the pharmacokinetics of bevacizumab and various dosing strategies for this agent in paediatric patients.

Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure.

Long-acting (LA) cabotegravir demonstrated superior efficacy versus daily oral standard-of-care for HIV-1 preexposure prophylaxis. This phase 1 study assessed safety, tolerability, pharmacokinetics, and acceptability of cabotegravir in 47 HIV-negative adult Chinese men at low risk of acquiring HIV-1. Participants received once-daily oral cabotegravir 30 mg for 4 weeks and, after a 1-week washout, five 600-mg (3-mL) intramuscular cabotegravir LA injections at weeks 5, 9, 17, 25, and 33. Pharmacokinetic plasma samples were intensively collected on day 27 (n = 17) and sparsely collected before each injection until 56 weeks after final injection (n = 47). Cabotegravir LA injections were acceptable and well tolerated. Common adverse events included injection site pain, injection site swelling, and upper respiratory tract infection. No drug-related serious adverse events or deaths occurred. Mean cabotegravir concentration remained above 1.33 μg/mL (8× in vitro protein-adjusted concentration for 90% of the maximum inhibition of viral growth [PA-IC90]) before each injection and above 0.166 μg/mL (PA-IC90) for >32 weeks after final injection. Trough concentrations remained above PA-IC90 in nearly all participants and showed minimal accumulation. Noncompartmental pharmacokinetic analysis was performed. Geometric mean of terminal half-life was 1.89 and 47 days after oral and LA dosing, respectively. Cabotegravir concentrations were estimated to remain quantifiable for 48.7 weeks after final injection. Steady-state area under the concentration-time curve (AUC), peak concentration, trough concentration, terminal half-life, time to peak concentration, and apparent clearance after cabotegravir oral and LA dosing were similar to those estimated in non-Asian men in historical studies. These results support further clinical development of cabotegravir LA in China. (This study has been registered at ClinicalTrials.gov under registration no. NCT03422172.).

Relebactam is a small-molecule β-lactamase inhibitor developed as a fixed-dose combination with imipenem/cilastatin. The pharmacokinetics of relebactam and imipenem across 10 clinical studies were analyzed using data from adult healthy volunteers and patients with bacterial infections. Renal function estimated by creatinine clearance significantly affected the clearance of both compounds, whereas weight and health status were of less clinical significance. Simulations were used to calculate probability of joint target attainment (ratio of free drug area under the curve from 0 to 24 hours to minimum inhibitory concentration (MIC) for relebactam and percentage of time the free drug concentration exceeded the MIC for imipenem) for the proposed imipenem/relebactam dose of 500/250 mg, with adjustments for patients with renal impairment, administered as a 30-minute intravenous infusion four times daily. These dosing regimens provide sufficient antibacterial coverage (MIC ≤ 4 μg/mL) for all renal groups.

Dose-dependent reductions in hepatitis B virus (HBV) RNA, DNA, and viral proteins following bepirovirsen administration were observed in HepG2.2.15 cells. In HBV-transgenic mice treated at 50 mg/kg/wk, hepatic HBV RNA and DNA were reduced by 90% and 99%, respectively. Subsequently, a phase 1 first-in-human study assessed pharmacokinetics and tolerability of single (75-450 mg) and multiple (150-450 mg on days 1, 4, 8, 11, 15, and 22) subcutaneous bepirovirsen doses in 96 healthy volunteers. Bepirovirsen at all dose levels was rapidly absorbed (maximum plasma concentration 3-8 hours after dosing), rapidly distributed to peripheral tissues, and slowly eliminated (median plasma terminal half-life: 22.5-24.6 days across cohorts). Plasma exposure (dose-proportional at 150-450 mg) and concentration-time profiles were similar following the first and sixth doses, suggesting little to no plasma accumulation (steady state achieved by day 22). Renal elimination of full-length bepirovirsen accounted for <2% of the total dose. Across the single and multiple dose cohorts, 197 treatment-emergent adverse events were reported, with 99% and 65% classified as mild in severity and local injection site reactions, respectively. In conclusion, bepirovirsen showed an acceptable safety profile in humans with observed pharmacokinetics consistent with the chemical class, warranting further evaluation of bepirovirsen in chronic HBV infection.

Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study.

Cabotegravir long-acting (LA) intramuscular (IM) injection is being investigated for HIV preexposure prophylaxis due to its potent antiretroviral activity and infrequent dosing requirement. A subset of healthy adult volunteers participating in a Phase I study assessing cabotegravir tissue pharmacokinetics underwent serial magnetic resonance imaging (MRI) to assess drug depot localization and kinetics following a single cabotegravir LA IM targeted injection.

Cabotegravir is an integrase strand transfer inhibitor in clinical development as long-acting (LA) injectable HIV preexposure prophylaxis.

To characterize cabotegravir population pharmacokinetics using data from phase 1, 2 and 3 studies and evaluate the association of intrinsic and extrinsic factors with pharmacokinetic variability.

A randomized, partial-blind, repeat-dose, 3-period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open-label 400-mg dose of the positive control moxifloxacin, with a 21-day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day -1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3-fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2-sided 90% confidence intervals for ΔΔQTcF (difference in time-matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization.

Bevacizumab is approved for various cancers. This analysis aimed to comprehensively evaluate bevacizumab pharmacokinetics and the influence of patient variables on bevacizumab pharmacokinetics.

The mTORC1 inhibitor everolimus (Afinitor/RAD001) has been approved for multiple cancer indications, including ER(+)/HER2(-) metastatic breast cancer. However, the combination of everolimus with the dual PI3K/mTOR inhibitor BEZ235 was shown to be more efficacious than either everolimus or BEZ235 alone in preclinical models. Herein, we describe a male breast cancer (MBC) patient who was diagnosed with hormone receptor-positive (HR(+))/HER2(-) stage IIIA invasive ductal carcinoma and sequentially treated with chemoradiotherapy and hormonal therapy. Upon the development of metastases, the patient began a 200 mg twice-daily BEZ235 and 2.5 mg weekly everolimus combination regimen. The patient sustained a prolonged stable disease of 18 mo while undergoing the therapy, before his tumor progressed again. Therefore, we sought to both better understand MBC and investigate the underlying molecular mechanisms of the patient's sensitivity and subsequent resistance to the BEZ235/everolimus combination therapy. Genomic and immunohistochemical analyses were performed on samples collected from the initial invasive ductal carcinoma pretreatment and a metastasis postprogression on the BEZ235/everolimus combination treatment. Both tumors were relatively quiet genomically with no overlap to recurrent MBC alterations in the literature. Markers of PI3K/mTOR pathway hyperactivation were not identified in the pretreatment sample, which complements previous reports of HR(+) female breast cancers being responsive to mTOR inhibition without this activation. The postprogression sample, however, demonstrated greater than fivefold increased estrogen receptor and pathogenesis-related protein expression, which could have constrained the PI3K/mTOR pathway inhibition by BEZ235/everolimus. Overall, these analyses have augmented the limited episteme on MBC genetics and treatment.

Cabotegravir is an investigational integrase inhibitor in development for the treatment and pre-exposure prophylaxis of HIV-1 infection. Liver disease is a major cause of morbidity and mortality in HIV-infected individuals and can impact the pharmacokinetics (PK) of HIV medications. This phase 1 study evaluated the PK of cabotegravir in individuals with moderate hepatic impairment (n = 8) versus healthy controls (n = 8). Participants received a single oral cabotegravir 30-mg tablet and underwent PK sampling to determine total and unbound plasma cabotegravir concentrations. Calculated geometric least-squares mean ratios (90% confidence intervals) for individuals with hepatic impairment versus healthy controls were 0.73 (0.50-1.06) for AUC0-∞ , 0.69 (0.51-0.93) for Cmax , 1.40 (0.80-2.46) for unbound concentration (CU) 2 hours postdose, 1.55 (0.82-2.94) for CU at 24 hours, 2.14 (1.57-2.90) for unbound fraction (FU) at 2 hours, and 1.90 (1.14-3.18) for FU at 24 hours. Adverse events (AEs) occurred in 2 individuals with hepatic impairment and 3 healthy controls and were grade 1/2 in severity. No participant discontinued because of AEs. Increased FU resulted in a modest decrease in total plasma exposure not considered clinically relevant. We conclude that cabotegravir may be administered without dose adjustment in patients with mild to moderate hepatic impairment.

Cabotegravir is an integrase inhibitor in clinical development for the treatment and prevention of HIV infection using oral tablets for short-term, lead-in use before subsequent administration of a long-acting injectable formulation. This phase 1, single-center, randomized, 2 × 2 crossover study evaluated the effect of a high-fat meal on the pharmacokinetics (PK) of oral cabotegravir. Healthy adults received oral cabotegravir 30 mg as a single dose on 2 separate occasions, either after fasting or following a high-fat meal (∼53% fat, ∼870 kcal). Safety evaluations and serial PK samples were collected, and a mixed-effects model was used to determine within-participant treatment comparison of noncompartmental PK parameters. Twenty-four patients were enrolled and had a mean body mass index of 25.6 kg/m2 ; 67% were male. Compared with the fasting state, coadministration of cabotegravir with a high-fat meal increased plasma cabotegravir area under the concentration-time curve and maximal drug concentration, each by 14%. The slight 14% to 17% increase in exposure associated with a high-fat, high-calorie meal was not considered clinically significant. No grade 3/4 adverse events (AEs), drug-related AEs, or AEs leading to discontinuation were reported.