The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK), and pharmacodynamics (PD) of three tenofovir (TFV) gels for rectal application. The vaginal formulation (VF) gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF) gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF) gel was also evaluated in the CHARM-01 study.

Vaginal tenofovir (TFV) 1% gel may reduce incident HIV-1 and herpes simplex virus 2 infection. Pregnancy may increase risk of HIV acquisition, and incident HIV in pregnancy potentiates perinatal HIV transmission. Our objective was to investigate the safety and pharmacokinetics of seven days of TFV 1% vaginal gel in term and near-term pregnancy.

Intravaginal rings (IVRs) for HIV pre-exposure prophylaxis (PrEP) theoretically overcome some adherence concerns associated with frequent dosing that can occur with oral or vaginal film/gel regimens. An innovative pod-IVR, composed of an elastomer scaffold that can hold up to 10 polymer-coated drug cores (or "pods"), is distinct from other IVR designs as drug release from each pod can be controlled independently. A pod-IVR has been developed for the delivery of tenofovir (TFV) disoproxil fumarate (TDF) in combination with emtricitabine (FTC), as daily oral TDF-FTC is the only Food and Drug Administration (FDA)-approved regimen for HIV PrEP. A triple combination IVR building on this platform and delivering TDF-FTC along with the antiretroviral (ARV) agent maraviroc (MVC) also is under development.

Global efforts aimed at preventing human immunodeficiency virus type one (HIV-1) infection in vulnerable populations appear to be stalling, limiting our ability to control the epidemic. Long-acting, controlled drug administration from subdermal implants holds significant potential by reducing the compliance burden associated with frequent dosing. We, and others, are exploring the development of complementary subdermal implant technologies delivering the potent prodrug, tenofovir alafenamide (TAF). The current report addresses knowledge gaps in the preclinical pharmacology of long-acting, subdermal TAF delivery using several mouse models. Systemic drug disposition during TAF implant dosing was explained by a multi-compartment pharmacokinetic (PK) model. Imaging mass spectrometry was employed to characterize the spatial distribution of TAF and its principal five metabolites in local tissues surrounding the implant. Humanized mouse studies determined the effective TAF dose for preventing vaginal and rectal HIV-1 acquisition. Our results represent an important step in the development of a safe and effective TAF implant for HIV-1 prevention.

Most human immunodeficiency virus (HIV) infections occur in cisgender women in resource-limited settings. In women, self-protection with emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (FTC/TDF-PrEP) constitutes a major pillar of HIV prevention. However, clinical trials in women had inconsistent outcomes, sparking uncertainty about adherence requirements and reluctance in evaluating on-demand regimens. We analyzed data from published FTC/TDF-PrEP trials to establish efficacy ranges in cisgender women. In a 'bottom-up' approach, we modeled hypotheses in the context of risk-group-specific, adherence-efficacy profiles and challenged those hypotheses with clinical data. We found that different clinical outcomes were related to the proportion of women taking the product, allowing coherent interpretation of the data. Our analysis showed that 90% protection was achieved when women took some product. We found that hypotheses of putative male/female differences were either not impactful or statistically inconsistent with clinical data. We propose that differing clinical outcomes could arise from pill-taking behavior rather than biological factors driving specific adherence requirements in cisgender women.

The effectiveness of oral emtricitabine (FTC)/tenofovir (TFV) disoproxil fumarate-based HIV pre-exposure prophylaxis (PrEP) depends on adherence. Pharmacologic measures help interpret patterns and predictors of PrEP adherence.

Measurement of immune mediators and antimicrobial activity in female genital tract secretions may provide biomarkers predictive of risk for HIV-1 acquisition and surrogate markers of microbicide safety. However, optimal methods for sample collection do not exist. This study compared collection methods.

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.

Tenofovir (TFV) is used in combination with other antiretroviral drugs for human immunodeficiency virus (HIV) treatment and prevention. TFV requires two phosphorylation steps to become pharmacologically active; however, the kinases that activate TFV in cells and tissues susceptible to HIV infection have yet to be identified. Peripheral blood mononuclear cells (PBMC), vaginal, and colorectal tissues were transfected with siRNA targeting nucleotide kinases, incubated with TFV, and TFV-monophosphate (TFV-MP) and TFV-diphosphate (TFV-DP) were measured using mass spectrometry-liquid chromatography. Adenylate kinase 2 (AK2) performed the first TFV phosphorylation step in PBMC, vaginal, and colorectal tissues. Interestingly, both pyruvate kinase isozymes, muscle (PKM) or liver and red blood cell (PKLR), were able to phosphorylate TFV-MP to TFV-DP in PBMC and vaginal tissue, while creatine kinase, muscle (CKM) catalyzed this conversion in colorectal tissue. In addition, next-generation sequencing of the Microbicide Trials Network MTN-001 clinical samples detected 71 previously unreported genetic variants in the genes encoding these kinases. In conclusion, our results demonstrate that TFV is activated in a compartment-specific manner. Further, genetic variants have been identified that could negatively impact TFV activation, thereby compromising TFV efficacy in HIV treatment and prevention.

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

Globally, women bear an uneven burden for sexual HIV acquisition. Results from two clinical trials evaluating intravaginal rings (IVRs) delivering the antiretroviral agent dapivirine have shown that protection from HIV infection can be achieved with this modality, but high adherence is essential. Multipurpose prevention technologies (MPTs) can potentially increase product adherence by offering protection against multiple vaginally transmitted infections and unintended pregnancy. Here we describe a coitally independent, long-acting pod-IVR MPT that could potentially prevent HIV and HSV infection as well as unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir alafenamide hemifumarate (TAF2) to prevent HIV, acyclovir (ACV) to prevent HSV, and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved hormonal contraceptives, were evaluated in pigtailed macaques (N = 6) over 35 days. Pod IVRs were exchanged at 14 days with the only modification being lower ENG release rates in the second IVR. Plasma progesterone was monitored weekly to determine the effect of ENG/EE on menstrual cycle. The mean in vivo release rates (mg d-1) for the two formulations over 30 days ranged as follows: TAF2 0.35-0.40; ACV 0.56-0.70; EE 0.03-0.08; ENG (high releasing) 0.63; and ENG (low releasing) 0.05. Mean peak progesterone levels were 4.4 ± 1.8 ng mL-1 prior to IVR insertion and 0.075 ± 0.064 ng mL-1 for 5 weeks after insertion, suggesting that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF2 and ACV release rates and resulting vaginal tissue drug concentrations (medians: TFV, 2.4 ng mg-1; ACV, 0.2 ng mg-1) may be sufficient to protect against HIV and HSV infection, respectively. This proof of principle study demonstrates that MPT-pod IVRs could serve as a potent biomedical prevention tool to protect women's sexual and reproductive health and may increase adherence to HIV PrEP even among younger high-risk populations.

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 (CAB) is an integrase strand-transfer inhibitor of HIV that has proven effective for HIV treatment and prevention in a long-acting injectable formulation, typically preceded by an oral formulation lead-in phase. Previous in vitro studies have demonstrated that CAB is primarily metabolized via glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9. In this study, we performed next-generation sequencing of genomic DNA isolated from the HPTN 077 participants to explore the variants within UGT1A1 and UGT1A9. Additionally, to enable correlation of UGT1A1 and UGT1A9 genotypes with plasma CAB-glucuronide levels, we quantified glucuronidated CAB following both oral administration of CAB and intramuscular injection of long-acting CAB. From these studies, 48 previously unreported variants of UGT1A1 and UGT1A9 were detected. Notably, 5/68 individuals carried a UGT1A1 454C>A variant that resulted in amino acid substitution P152T, and the use of in silico tools predicted a deleterious effect of the P152T substitution. Thus, the impact of this mutant on a range of UGT1A1 substrates was tested using a COS-7 cell-based assay. The glucuronide conjugates of CAB, dolutegravir, and raltegravir, were not formed in the COS-7 cells expressing the UGT1A1 P152T mutant. Further, formation of glucuronides of raloxifene and 7-ethyl-10-hydroxycamptothecin were reduced in the cells expressing the UGT1A1 P152T mutant. Using the same approach, we tested the activities of two UGT1A9 mutants, UGT1A9 H217Y and UGT1A9 R464G, and found that these mutations were tolerated and decreased function, respectively. These data provide insight into previously unreported genetic variants of UGT1A1 and UGT1A9.

Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.

The efficacy of pre-exposure prophylaxis (PrEP) in HIV will diminish with poor adherence; pharmacologic measures of drug exposure have proven critical to PrEP trial interpretation. We assessed drug exposure in hair against other pharmacologic and more routinely used measures to assess pill-taking.

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.

The L-type calcium channel gene, CACNA1C, is a validated risk gene for schizophrenia and the target of calcium channel blockers. Carriers of the risk-associated genotype (rs1006737 A allele) have increased frontal cortical activity during working memory and higher CACNA1C mRNA expression in the prefrontal cortex. The aim of this study was to determine how the brain-penetrant calcium channel blocker, nimodipine, changes brain activity during working memory and other cognitive and emotional processes. We conducted a double-blind randomized cross-over pharmacoMRI study of a single 60 mg dose of oral nimodipine solution and matching placebo in healthy men, prospectively genotyped for rs1006737. With performance unchanged, nimodipine significantly decreased frontal cortical activity by 39.1% and parietal cortical activity by 42.8% during the N-back task (2-back > 0-back contrast; PFWE < 0.05; n = 28). Higher peripheral nimodipine concentrations were correlated with a greater decrease in activation in the frontal cortex. Carriers of the risk-associated allele, A (n = 14), had a greater decrease in frontal cortical activation during working memory compared to non-risk allele carriers. No differences in brain activation were found between nimodipine and placebo for other tasks. Future studies should be conducted to test if the decreased cortical brain activity after nimodipine is associated with improved working memory performance in patients with schizophrenia, particularly those who carry the risk-associated genotype. Furthermore, changes in cortical activity during working memory may be a useful biomarker in future trials of L-type calcium channel blockers.