Pharmacokinetics and pharmacodynamics of TMC207 and its N-desmethyl metabolite in a murine model of tuberculosis.

TMC207 is a first-in-class diarylquinoline with a new mode of action against mycobacteria targeting the ATP synthase. It is metabolized to an active derivative, N-desmethyl TMC207, and both compounds are eliminated with long terminal half-lives (50 to 60 h in mice) reflecting slow release from tissues such as lung and spleen. In vitro, TMC207 is 5-fold more potent against Mycobacterium tuberculosis than N-desmethyl TMC207, and the effects of the two compounds are additive.

TMC310911, a novel human immunodeficiency virus type 1 protease inhibitor, shows in vitro an improved resistance profile and higher genetic barrier to resistance compared with current protease inhibitors.

TMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. TMC310911 has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC(50)], 14 nM) and a wide spectrum of recombinant HIV-1 clinical isolates, including multiple-PI-resistant strains with decreased susceptibility to currently approved PIs (fold change [FC] in EC(50), >10). For a panel of 2,011 recombinant clinical isolates with decreased susceptibility to at least one of the currently approved PIs, the FC in TMC310911 EC(50) was ≤ 4 for 82% of isolates and ≤ 10 for 96% of isolates.

Clinical pharmacokinetics and pharmacodynamics of etravirine.

Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection. It has a high genetic barrier to the emergence of viral resistance, and maintains its antiviral activity in the presence of common NNRTI mutations. The pharmacokinetics of etravirine in HIV-infected patients at the recommended dosage of 200 mg twice daily demonstrates moderate intersubject variability and no time dependency.

Absorption, metabolism, and excretion of darunavir, a new protease inhibitor, administered alone and with low-dose ritonavir in healthy subjects.

Absorption, metabolism, and excretion of darunavir, an inhibitor of human immunodeficiency virus protease, was studied in eight healthy male subjects after a single oral dose of 400 mg of [(14)C]darunavir given alone (unboosted subjects) or with ritonavir [100 mg b.i.d.

Real life juvenile toxicity case studies: the good, the bad and the ugly.

With the growing experience in the conduct of juvenile toxicity studies for multiple classes of compound, the 'case-by-case' approach has become under much more pressure. Instead, a general screen or 'standard design' is now commonly expected by regulatory authorities with more routine inclusion of neurological and reproductive assessments. Minor modifications or additions can be made to the design to address specific questions according to the class of drug or intended clinical use.

Oral bioavailability and multiple dose tolerability of an antisense oligonucleotide tablet formulated with sodium caprate.

In vivo study was performed to determine the tolerability and pharmacokinetics of ISIS 104838, a phosphorothioate antisense oligonucleotide targetting human tumour necrosis factor alpha (TNF-alpha) mRNA, following multi-dose administration via intravenous and oral routes. Oral tablet formulations of ISIS 104838 were pre-formulated with the permeation enhancer, sodium caprate, in an enteric-coated solid dosage form. The average plasma bioavailability of ISIS 104838 was 1.

Effect of sodium caprate on the intestinal absorption of two modified antisense oligonucleotides in pigs.

Sodium caprate, a medium chain fatty acid, is known to enhance the transport of drugs across the intestinal mucosa in cell culture systems and small animal species. The aim of the present study was to evaluate the effect of this enhancer on the oral absorption of two chemically modified antisense oligonucleotides ISIS 2503 (phosphorothioate) and ISIS 104838 (methoxyethyl modified phosphorothioate) using an intra-intestinal catheterised pig model. Sodium caprate at doses 25, 50 and 100 mg/kg was effective in enhancing systemic delivery of both antisense chemistries.