Optimisation of treatments for oral Neisseria gonorrhoeae infection: Pharmacokinetics Study (STI-PK project) - study protocol for non-randomised clinical trial.

INTRODUCTION: Neisseria gonorrhoeae infections are common and incidence increasing. Oropharyngeal infections are associated with greater treatment failure compared with other sites and drive transmission to anogenital sites through saliva. Gonococcal resistance is increasing and new treatments are scarce, therefore, clinicians must optimise currently available and emerging treatments in order to have efficacious therapeutic options. This requires pharmacokinetic data from the oral cavity/oropharynx, however, availability of such information is currently limited. METHODS AND ANALYSIS: Healthy male volunteers (participants) recruited into the study will receive single doses of either ceftriaxone 1 g, cefixime 400 mg or ceftriaxone 500 mg plus 2 g azithromycin. Participants will provide samples at 6-8 time points (treatment regimen dependent) from four oral sites, two oral fluids, one anorectal swab and blood. Participants will complete online questionnaires about their medical history, sexual practices and any side effects experienced up to days 5-7. Saliva/oral mucosal pH and oral microbiome analysis will be undertaken. Bioanalysis will be conducted by liquid chromatography-mass spectrometry. Drug concentrations over time will be used to develop mathematical models for optimisation of drug dosing regimens and to estimate pharmacodynamic targets of efficacy. ETHICS AND DISSEMINATION: This study was approved by Royal Melbourne Hospital Human Research Ethics Committee (60370/MH-2021). The study results will be submitted for publication in peer-reviewed journals and reported at conferences. Summary results will be sent to participants requesting them. All data relevant to the study will be included in the article or uploaded as supplementary information. TRIAL REGISTRATION NUMBER: ACTRN12621000339853.

CNS effects of a CCR5 inhibitor in HIV-infected subjects: a pharmacokinetic and cerebral metabolite study.

BACKGROUND: We conducted a pharmacokinetic and in vivo cerebral (1)H magnetic resonance spectroscopy ((1)H-MRS) study to assess CSF exposure and cerebral metabolite ratios (CMRs) following maraviroc intensification. METHODS: HIV-infected neurologically asymptomatic adults receiving tenofovir, emtricitabine and lopinavir/ritonavir with plasma HIV RNA <50 copies/mL were eligible and received intensified therapy with 150 mg of maraviroc twice daily. (1)H-MRS was performed in several cerebral locations, including the right basal ganglia (RBG), to assess CMRs, including N-acetyl aspartate/creatine (NAA/Cr), at baseline and after 14 days. Subsequently, on day 15, blood samples were obtained to determine plasma concentrations of maraviroc pre-dose (C(trough)) and then paired blood and CSF samples were collected at 4 or 6 h post-dose. Associations between maraviroc exposure, clinical parameters and changes to CMRs were evaluated. TRIAL REGISTRY: ClinicalTrials.gov (http://clinicaltrials.gov/ct2/show/NCT00982878). RESULTS: Twelve subjects (75% male) participated with a mean (SD) CD4+ cell count of 503 (199) cells/µL. Mean (SD) maraviroc plasma concentrations at pre-dose, 4 h post-dose and 6 h post-dose were 337 (74), 842 (174) and 485 (100) ng/mL and CSF concentrations at 4 h post-dose and 6 h post-dose were 7.5 (1.3) and 5.1 (1.2) ng/mL. The mean maraviroc CSF : plasma ratio (range) was 1.01% (0.57%-1.61%). An increase of 14.8% was observed for the RBG NAA/Cr ratio, which was significantly associated with higher maraviroc plasma C(trough) (P = 0.05, r = 0.61), but not CSF concentration (P = 0.16, r = 0.46). CONCLUSIONS: After 14 days of maraviroc intensification, small increases in cerebral metabolite markers of neuronal integrity (NAA/Cr ratios) were observed and are associated with maraviroc plasma C(trough).

The effects of a nucleoside-sparing antiretroviral regimen on the pharmacokinetics of ritonavir-boosted darunavir in HIV type-1-infected patients.

BACKGROUND: Nucleoside-sparing combination antiretroviral therapy (cART) regimens might be an attractive therapeutic option for HIV type-1 (HIV-1)-infected patients; however, the pharmacokinetic profiles of such regimens are frequently unknown. METHODS: Fourteen HIV-1-infected patients (age 21-55 years, 64% male) on stable cART with plasma HIV RNA <50 copies/ml entered this Phase I pharmacokinetic study. In period 1, patients received tenofovir/emtricitabine/-darunavir/ritonavir (300/200/800/100 mg) all once daily. During period 2, raltegravir 400 mg twice daily was added to the regimen and in period 3 tenofovir/emtricitabine was discontinued. At steady state, intensive pharmacokinetic sampling was undertaken. Differences in the geometric mean ratio (GMR) for pharmacokinetic parameters between periods 2 versus 1 and period 3 versus 1 were assessed for darunavir and ritonavir (period 3 versus 2 for raltegravir). RESULTS: No statistically significant differences in pharmacokinetic parameters were observed between period 2 versus period 1. During period 3, darunavir GMR (95% confidence interval) values for trough and maximum plasma concentration (C(trough) and C(max)), area under the plasma concentration-time curve (AUC) and elimination half-life (t(1/2)) were 0.64 ng/ml (0.44-0.93), 1.05 ng/ml (0.90-1.24), 0.92 ng h/ml (0.78-1.08) and 0.69 h (0.46-1.05), respectively, when compared with period 1. No statistically significant changes were observed in ritonavir or raltegravir pharmacokinetic parameters. Darunavir C(trough)<550 ng/ml (the minimum effective concentration for protease-resistant HIV viral isolates) was observed in four patients during period 3 only. No clinically significant safety concerns were reported. CONCLUSIONS: Darunavir C(trough) is reduced by 36% when administered without tenofovir/emtricitabine in HIV-1-infected patients. This interaction might be of clinical significance in the management of individuals with protease-resistant HIV viral isolates.