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.

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.

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.).

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.

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