Marie-Paule Bouche

Pharmacokinetics and Disposition of Rilpivirine (TMC278) Nanosuspension as a Long-Acting Injectable Antiretroviral Formulation

ABSTRACT The next-generation human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) was administered in rats and dogs as single intramuscular (IM) or subcutaneous (SC) injections, formulated as a 200-nm nanosuspension. The plasma pharmacokinetics, injection site concentrations, disposition to lymphoid tissues, and tolerability were evaluated in support of its potential use as a once-monthly antiretroviral agent in humans. Rilpivirine plasma concentration-time profiles showed sustained and dose-proportional release over 2 months in rats and over 6 months in dogs. The absolute bioavailability approached 100%, indicating a complete release from the depot, in spite of rilpivirine concentrations still being high at the injection site(s) 3 months after administration in dogs. For both species, IM administration was associated with higher initial peak plasma concentrations and a more rapid washout than SC administration, which resulted in a stable plasma-concentration profile over at least 6 weeks in dogs. The rilpivirine concentrations in the lymph nodes draining the IM injection site exceeded the plasma concentrations by over 100-fold 1 month after administration, while the concentrations in the lymphoid tissues decreased to 3- to 6-fold the plasma concentrations beyond 3 months. These observations suggest uptake of nanoparticles by macrophages, which generates secondary depots in these lymph nodes. Both SC and IM injections were generally well tolerated and safe, with observations of a transient inflammatory response at the injection site. The findings support clinical investigations of rilpivirine nanosuspension as a long-acting formulation to improve adherence during antiretroviral therapy and for preexposure prophylaxis.

A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV–negative volunteers

AIMS Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV. Proton pump inhibitors and H(2)-antagonists are frequently used in the HIV-negative-infected population, and drug-drug interactions have been described with other antiretrovirals. This study evaluated the effect of steady-state omeprazole and ranitidine on the pharmacokinetics of a single dose of etravirine. METHODS In an open-label, randomized, one-way, three-period crossover trial, HIV-negative volunteers randomly received a single dose of 100 mg etravirine alone (treatment A); 11 days of 150 mg ranitidine b.i.d. (treatment B); and 11 days of 40 mg omeprazole q.d. (treatment C). A single dose of 100 mg etravirine was co-administered on day 8 of sessions 2 and 3. Each session was separated by a 14-day wash-out. RESULTS Nineteen volunteers (seven female) participated. When a single dose of etravirine was administered in the presence of steady-state ranitidine, etravirine least squares means ratios (90% confidence interval) for AUC(last) and C(max) were 0.86 (0.76, 0.97) and 0.94 (0.75, 1.17), respectively, compared with administration of etravirine alone. When administered with steady-state omeprazole, these values were 1.41 (1.22, 1.62) and 1.17 (0.96, 1.43), respectively. Co-administration of a single dose of etravirine and ranitidine or omeprazole was generally safe and well tolerated. CONCLUSIONS Ranitidine slightly decreased etravirine exposure, whereas omeprazole increased it by approximately 41%. The increased exposure of etravirine when co-administered with omeprazole is attributed to CYP2C19 inhibition. Considering the favourable safety profile of etravirine, these changes are not clinically relevant. Etravirine can be co-administered with proton pump inhibitors and H(2) antagonists without dose adjustments.

Only Carbon Dioxide Absorbents Free of Both NaOH and KOH Do Not Generate Compound A during In Vitro Closed-system Sevoflurane Evaluation of Five Absorbents

BackgroundInsufficient data exist on the production of compound A during closed-system sevoflurane administration with newer carbon dioxide absorbents. MethodsA modified PhysioFlex apparatus (Dräger, Lübeck, Germany) was connected to an artificial test lung (inflow at the top of the bellow ≅ 160 ml/min CO2; outflow at the Y piece of the lung model ≅ 200 ml/min, simulating oxygen consumption). Ventilation was set to obtain an end-tidal carbon dioxide partial pressure of approximately 40 mmHg. Various fresh carbon dioxide absorbents were used: Sodasorb (n = 6), Sofnolime (n = 6), and potassium hydroxide (KOH)–free Sodasorb (n = 7), Amsorb (n = 7), and lithium hydroxide (n = 7). After baseline analysis, liquid sevoflurane was injected into the circuit by syringe pump to obtain 2.1% end-tidal concentration for 240 min. At baseline and at regular intervals thereafter, end-tidal carbon dioxide partial pressure, end-tidal sevoflurane concentration, and canister inflow (T°in) and canister outflow (T°out) temperatures were measured. To measure compound Ainsp concentration in the inspired gas of the breathing circuit, 2-ml gas samples were taken and analyzed by capillary gas chromatography plus mass spectrometry. ResultsThe median (minimum–maximum) highest compound Ainsp concentrations over the entire period were, in decreasing order: 38.3 (28.4–44.2)* (Sofnolime), 30.1 (23.9–43.7) (KOH-free Sodasorb), 23.3 (20.0–29.2) (Sodasorb), 1.6 (1.3–2.1)* (lithium hydroxide), and 1.3 (1.1–1.8)* (Amsorb) parts per million (*P < 0.01 vs. Sodasorb). After reaching their peak concentration, a decrease for Sofnolime, KOH-free Sodasorb, and Sodasorb until 240 min was found. The median (minimum–maximum) highest values for T°out were 39 (38–40), 40 (39–42), 41 (40–42), 46 (44–48)*, and 39 (38–41) °C (*P < 0.01 vs. Sodasorb), respectively. ConclusionsWith KOH-free (but sodium hydroxide [NaOH]–containing) soda limes even higher compound A concentrations are recorded than with standard Sodasorb. Only by eliminating KOH as well as NaOH from the absorbent (Amsorb and lithium hydroxide) is no compound A produced.

Powder for reconstitution of the anti-HIV-1 drug TMC278 - Formulation development, stability and animal studies

Powders for reconstitution of the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 with low water solubility were developed by using a spray-dry technology. Their flexible dosing ability makes them suitable for patients looking for a different approach for antiretroviral (ARV) therapy. The selection of formulation excipients was based on their potential to create and maintain supersaturation solubility of TMC278 in 0.01 M HCl. Suitable water-soluble carriers for TMC278 were selected by a supersaturation screening to formulate powders for reconstitution by spray-drying. The selected powders for reconstitution were compared to clinical tablets of TMC278.HCl, in vitro using dissolution and stability testing, and in vivo through administration to beagle dogs, fed immediately after dosing. The spray-dried powders for reconstitution made up of TMC278/PVP-VA 64 1:9 (w/w) and TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w) showed ease of suspendability, nearly complete dissolution of the drug and acceptable stability after one month storage at 25 and 40 degrees C. In dogs, TMC278 was more slowly absorbed from tablets than from the suspended powders for reconstitution. Compared to the tablet, the relative bioavailability obtained with the powders ranged between 69% and 89% for TMC278/PVP-VA 64 1:9 (w/w) and between 85% and 157% for TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w). The absence of differences in vivo and in vitro between the powders made an eventual choice very difficult, yet their advantageous in vivo behaviour and flexible dosing possibility may provide a starting point for paediatric formulations.

In Vitro Compound A Formation in a Computer- controlled Closed-circuit Anesthetic Apparatus Comparison with a Classical Valve Circuit

BackgroundFew data exist on compound A during sevoflurane anesthesia when using closed-circuit conditions and sodalime with modern computer-controlled liquid injection. MethodsA PhysioFlex apparatus (Dräger, Lübeck, Germany) was connected to an artificial test lung (inflow ≈ 160 ml/min carbon dioxide, outflow ≈ 200 ml/min, simulating oxygen consumption). Ventilation was set to obtain an end-tidal carbon dioxide partial pressure (Petco2) ≈ 40 mmHg. Canister inflow (T°in) and outflow (T°out) temperatures were measured. Fresh sodalime and charcoal were used. After baseline analysis, sevoflurane concentration was set at 2.1% end-tidal for 120 min. At baseline and at regular intervals thereafter, Petco2, end-tidal sevoflurane, T°in, and T°out were measured. For inspiratory and expiratory compound A determination, samples of 2-ml gas were taken. These data were compared with those of a classical valve–containing closed-circuit machine. Ten runs were performed in each set-up. ResultsInspired compound A concentrations increased from undetectable to peak at 6.0 (SD 1.3) and 14.3 (SD 2.5) ppm (P < 0.05), and maximal temperature in the upper outflow part of the absorbent canister was 24.3°C (SD 3.6) and 39.8°C (SD 1.2) (P < 0.05) in the PhysioFlex and valve circuit machines, respectively. Differences between the two machines in compound A concentrations and absorbent canister temperature at the inflow and outflow regions were significantly different (P < 0.05) at all times after 5 min. ConclusionCompound A concentrations in the high-flow (70 l/min), closed-circuit PhysioFlex machine were significantly lower than in conventional, valve-based machines during closed-circuit conditions. Lower absorbent temperatures, resulting from the high flow, appear to account for the lower compound A formation.