Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers

AbstractBackground and aimsLactulose is a common food ingredient and widely used as a treatment for constipation or hepatic encephalopathy and a substrate for hydrogen breath tests. Lactulose is fermented by the colon microbiota resulting in the production of hydrogen (H2). H2is a substrate for enteropathogens includingSalmonellaTyphimurium (S. Typhimurium) and increased H2production upon lactulose ingestion might favor the growth of H2-consuming enteropathogens. We aimed to analyze effects of single-dose lactulose ingestion on the growth of intrinsicEscherichia coli(E. coli), which can be efficiently quantified by plating and which share most metabolic requirements withS. Typhimurium.Methods32 healthy volunteers (18 females, 14 males) were recruited. Participants were randomized for single-dose ingestion of 50 g lactulose or 50 g sucrose (controls). After ingestion, H2in expiratory air and symptoms were recorded. Stool samples were acquired at days −1, 1 and 14. We analyzed 16S microbiota composition and abundance and characteristics ofE.coliisolates.ResultsLactulose ingestion resulted in diarrhea in 14/17 individuals. In 14/17 individuals, H2-levels in expiratory air increased by ≥20 ppm within 3 hours after lactulose challenge. H2-levels correlated with the number of defecations within 6 hours.E. coliwas detectable in feces of all subjects (2 x 102- 109CFU/g). However, the number ofE.colicolony forming units (CFU) on selective media did not differ between any time point before or after challenge with sucrose or lactulose. The microbiota composition also remained stable upon lactulose exposure.ConclusionIngestion of a single dose of 50 g lactulose does not significantly alterE.colidensity in stool samples of healthy volunteers. 50 g lactulose therefore seems unlikely to sufficiently alter growth conditions in the intestine for a significant predisposition to infection with H2-consuming enteropathogens such asS. Typhimurium (www.clinicaltrials.govNCT02397512).

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940 SAFETY, TOLERABILITY AND PHARMACOKINETICS OF THE HCV POLYMERASE INHIBITOR VCH-222 FOLLOWING SINGLE DOSE ADMINISTRATION IN HEALTHY VOLUNTEERS AND ANTIVIRAL ACTIVITY IN HCV-INFECTED INDIVIDUALS

Journal of Hepatology ◽

10.1016/s0168-8278(09)60942-9 ◽

2009 ◽

Vol 50 ◽

pp. S342 ◽

Cited By ~ 14

Author(s):

C. Cooper ◽

R. Larouche ◽

B. Bourgault ◽

N. Chauret ◽

L. Proulx

Keyword(s):

Single Dose ◽

Antiviral Activity ◽

Healthy Volunteers ◽

Dose Administration ◽

Single Dose Administration ◽

Polymerase Inhibitor

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Abstract 2009: ALX-0081 a Novel Anti-Thrombotic: Results of a Single-Dose Phase 1 Study in Healthy Volunteers and Further Development in Patients with Stable Angina Undergoing PCI

Circulation ◽

10.1161/circ.118.suppl_18.s_656-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Jozef Bartunek ◽

Emanuele Barbato ◽

Josefin-Beate Holz ◽

Kristof Vercruysse ◽

Hans Ulrichts ◽

...

Keyword(s):

Single Dose ◽

Healthy Volunteers ◽

Dose Escalation ◽

Stable Angina ◽

Thrombus Formation ◽

Phase 1 ◽

Controlled Study ◽

Double Blind ◽

Phase Ib ◽

Wide Range

Background : ALX-0081 is a bivalent Nanobody ® based on the variable domain of naturally occurring heavy-chain only antibodies. It binds with high affinity to the A1 domain of von Willebrand Factor (vWF) and thereby blocks the interactions between platelets and vascular collagen. It selectively prevents thrombus formation under high shear stress conditions. Aim : Test ALX-0081 single IV infusions (60 minutes) dosed from 0.5mg to 12mg total in 40 male healthy volunteers in double-blind, randomized, placebo controlled study and assess pharmacokinetic (PK), pharmacodynamic (PD), safety and immunogenicity. Results : ALX-0081 displayed non-linear pharmacokinetic properties, following a 2 compartment model. Ristocetin induced platelet aggregation (RIPA) was analyzed as marker for PD effect with full inhibition (defined as measured levels dropping <10%) observed at ALX-0081 concentrations of ~ 400ng/ml. All subjects dosed ≥ 2mg achieved full RIPA inhibition at 1h post-dosing for maximum of 12h. ALX-0081 treatment was well tolerated and safe, no signs of bleeding were reported and no immunogenic response was detected. Target related mild and transient reductions of vWF and FVIII plasma levels were observed and all events were fully reversible. Phase Ib study design : double-blind, randomized, placebo controlled, multiple ascending dose study. ALX-0081 added to standard anti-thrombotic regimen (ASA, clopidogrel, UFH) in patients with stable angina undergoing elective PCI. Single-dose escalation will be followed by multiple dosing (up to 4 doses in 24h). Dose escalation will be guided by safety and efficacy marker. Endpoints: safety, pharmacological profile, biomarker (RIPA, RICO and ACT) and early clinical outcome (MACE, IMR, molecular marker). Conclusion : ALX-0081 can be administered safely over a wide range of dose-regimen. First results of the phase Ib study in stable angina patients will be presented.

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