Dose- and Time-dependency of the Toxicity and Pharmacokinetic Profiles of Bedaquiline and Its N-desmethyl Metabolite in Dogs.

Bedaquiline (BDQ) is an antibiotic to treat pulmonary multidrug-resistant tuberculosis (MDR-TB). Studies up to 39 weeks were conducted orally in dogs to assess the toxicity and pharmacokinetics of BDQ and its N-desmethyl metabolite (D-BDQ). Phospholipidosis (PLD) seen in the monocytic phagocytic system was considered an adaptive change. Skeletal muscle, heart, stomach, liver, and pancreas toxicities with D-BDQ as the main contributor were associated with a less-than-dose-proportional increase in plasma exposure and an overproportional tissue uptake of BDQ and D-BDQ at high-dose levels. Tissue concentrations of BDQ and D-BDQ slowly decreased after lowering the dose, contributing to the recovery of the pathological findings. Treatment was better tolerated at mid-dose levels, characterized by a dose-proportional increase in plasma and tissue exposures. Treatment at a low dose, reaching exposures approximating therapeutic exposures, was without adverse effects and not associated with PLD. There was no evidence of delayed toxicities after treatment cessation. Intermittent dosing was better tolerated at high doses. Since MDR-TB patients are dosed within the linear plasma exposure range and plasma levels of BDQ and D-BDQ are similar or lower than in dogs, PLD and adverse findings related to tissue accumulation that occurred at high doses in dogs are unlikely to occur in humans.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of oral JNJ-64794964, a TLR-7 agonist, in healthy adults.

BACKGROUND: This Phase I, two-part, first-in-human study assessed safety/tolerability and pharmacokinetics/pharmacodynamics of single-ascending doses (SAD) and multiple doses (MD) of the oral toll-like receptor-7 agonist, JNJ-64794964 (JNJ-4964) in healthy adults. METHODS: In the SAD phase, participants received JNJ-4964 0.2 (N = 6), 0.6 (N = 6), 1.25 (N = 8) or 1.8 mg (N = 6) or placebo (N = 2/dose cohort) in a fasted state. Food effect was evaluated for the 1.25 mg cohort following ≥6 weeks washout. In the MD phase, participants received JNJ-4964 1.25 mg (N = 6) or placebo (N = 2) weekly (fasted) for 4 weeks. Participants were followed-up for 4 weeks. RESULTS: No serious adverse events (AEs) occurred. 10/34 (SAD) and 5/8 (MD) participants reported mild-to-moderate (≤Grade 2), transient, reversible AEs possibly related to JNJ-4964. Five (SAD) participants had fever/flu-like AEs, coinciding with interferon-α serum levels ≥100 pg/mL and lymphopenia (<1 × 109/L), between 24-48 h after dosing and resolving approximately 96 h after dosing. One participant (MD) had an asymptomatic Grade 1 AE of retinal exudates (cotton wool spots) during follow-up, resolving 6 weeks after observation. JNJ-4964 exhibited dose-proportional pharmacokinetics, with rapid absorption (tmax 0.5-0.75 h) and distribution, and a long terminal half-life (150-591 h). Overall, no significant differences in JNJ-4964 pharmacokinetic parameters were observed in the fed versus fasted state. JNJ-4964 dose-dependently and transiently induced cytokines with potential anti-HBV activity, including interferon-α, IP-10, IL-1 RA, and/or MCP-1, and interferon-stimulated genes (ISG15, MX1, and OAS1) in serum. CONCLUSIONS: In healthy adults, JNJ-4964 was generally well-tolerated, exhibited dose-proportional pharmacokinetics and induced cytokines/ISGs, with possible anti-HBV activity.

2,4-Diaminoquinazolines as Dual Toll-like Receptor (TLR) 7/8 Modulators for the Treatment of Hepatitis B Virus.

A novel series of 2,4-diaminoquinazolines was identified as potent dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target activity. The stereochemistry of the amino alcohol was found to influence the TLR7/8 selectivity with the ( R) isomer resulting in selective TLR8 agonism. Lead optimization toward a dual agonist afforded ( S)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexanol 31 as a potent analog, being structurally different from previously described dual agonists ( McGowan J. Med. Chem. 2016 , 59 , 7936 ). Pharmacokinetic and pharmacodynamic (PK/PD) studies revealed the desired high first pass profile aimed at limiting systemic cytokine activation. In vivo pharmacodynamic studies with lead compound 31 demonstrated production of cytokines consistent with TLR7/8 activation in mice and cynomolgus monkeys and ex vivo inhibition of hepatitis B virus (HBV).

Identification and Optimization of Pyrrolo[3,2-d]pyrimidine Toll-like Receptor 7 (TLR7) Selective Agonists for the Treatment of Hepatitis B.

Pyrrolo[3,2-d]pyrimidines were identified as a new series of potent and selective TLR7 agonists. Compounds were optimized for their activity and selectivity over TLR8. This presents an advantage over recently described scaffolds that have residual TLR8 activity, which may be detrimental to the tolerability of the candidate drug. Oral administration of the lead compound 54 effectively induced a transient interferon stimulated gene (ISG) response in mice and cynomolgus monkeys. We aimed for a high first pass effect, limiting cytokine induction systemically, and demonstrated the potential for the immunotherapy of viral hepatitis.

Novel Pyrimidine Toll-like Receptor 7 and 8 Dual Agonists to Treat Hepatitis B Virus.

Toll-like receptor (TLR) 7 and 8 agonists can potentially be used in the treatment of viral infections and are particularly promising for chronic hepatitis B virus (HBV) infection. An internal screening effort identified a pyrimidine Toll-like receptor 7 and 8 dual agonist. This provided a novel alternative over the previously reported adenine and pteridone type of agonists. Structure-activity relationship, lead optimization, in silico docking, pharmacokinetics, and demonstration of ex vivo and in vivo cytokine production of the lead compound are presented.

Safety and pharmacokinetics of the HIV-1 protease inhibitor TMC310911 coadministered with ritonavir in healthy participants: results from 2 phase 1 studies.

OBJECTIVES: To evaluate safety, tolerability, and pharmacokinetics of TMC310911, a novel human immunodeficiency virus type-1 protease inhibitor. METHODS: Healthy participants aged 18-55 years with body mass index 18-30 kg/m were enrolled in 2 phase 1 studies. In the first-in-human, single-dose study, 18 participants received placebo or TMC310911 (75-2000 mg) in the double-blind phase and 8 participants received 300 or 600 mg of TMC310911 [administered alone or with 100 mg ritonavir twice daily (bid)] in the subsequent open-label phase. The multiple-dose double-blind study included 5 successive treatment sessions wherein healthy participants received placebo or TMC310911 [300 mg bid, 600 mg once daily or 150 mg bid (plus 100 mg ritonavir bid), 900 mg bid (alone) or 300 mg bid (plus ritonavir 50 mg bid)]; in all sessions, TMC310911 and ritonavir were administered for 6 and 9 days, respectively. RESULTS: In the single-dose study, no dose-limiting toxicity was observed up to 2000 mg of TMC310911. Systemic exposure to TMC310911 generally increased in a dose-proportional manner after the single- or multiple-dose administrations. Coadministration of ritonavir increased the systemic exposure to TMC310911. The mean Cmax and area under plasma concentration-time curve values (single-dose: 1200 mg TMC310911) were higher under fasted conditions than in fed condition. In both studies, most treatment-emergent adverse events were related to gastrointestinal system. CONCLUSIONS: TMC310911 exhibited a linear pharmacokinetic profile after the single- (up to 2000 mg) and multiple-dose (up to 900 mg) administrations; ritonavir improved the pharmacokinetic profile of TMC310911. TMC310911 was generally safe and tolerable when administered with or without ritonavir.

Antiviral activity, pharmacokinetics, and safety of the HIV-1 protease inhibitor TMC310911, coadministered with ritonavir, in treatment-naive HIV-1-infected patients.

OBJECTIVES: TMC310911 is a novel HIV type-1 (HIV-1) protease inhibitor with broad in vitro antiviral activity. In this phase 2a, open-label randomized study, the antiviral activity, pharmacokinetics, and safety and tolerability of ritonavir-boosted TMC310911 was assessed. METHODS: In this study, treatment-naive HIV-1 patients (aged 18-60 years) received 1 of the 4 dosing regimens of TMC310911: 150 mg twice-daily (bid) (n = 8), 300 mg bid (n = 8), 75 mg bid (n = 9), or 300 mg once-daily (qd) (n = 8), for 14 days, all coadministered with 100 mg of ritonavir, as only antiretroviral therapy. RESULTS: The mean change from baseline in HIV-1 RNA (log10 copies per milliliter; primary efficacy endpoint) was -1.30 (75 mg bid), -1.14 (150 mg bid), -1.07 (300 mg bid), and -1.06 (300 mg qd) on day 8 and -1.53 (75 mg bid), -1.79 (150 mg bid), -1.69 (300 mg bid), and -1.55 (300 mg qd) on day 15. At steady state (day 14), the mean maximum plasma concentration and mean area under the plasma concentration-time curve from 0 to 12 hours tended to increase dose proportionally for bid doses; TMC310911 daily exposures for the 300 mg qd treatment and 150 mg bid treatment were comparable. The most common (≥ 10%) treatment-emergent adverse events were fatigue (27.3%) and nausea (12.1%); no deaths or serious treatment-emergent adverse events were reported in this study. CONCLUSIONS: Combination treatment with TMC310911 and ritonavir showed potent antiviral activity (>1.5 log10 copies/mL decrease in plasma HIV-1 RNA) at all evaluated doses, and treatment was generally safe and well tolerated.