A compartmental pharmacokinetic evaluation of long-acting rilpivirine in HIV-negative volunteers for pre-exposure prophylaxis.

Rilpivirine long-acting (RPV-LA) is a parenteral formulation enabling prolonged plasma exposure. We explored its multiple-compartment pharmacokinetics (PK) after a single dose, for pre-exposure prophylaxis. Sixty-six HIV-negative volunteers were enrolled: women received an intramuscular dose of 300, 600, or 1,200 mg, with plasma and genital levels measured to 84 days postdose; men receiving 600 mg had similar PK determined in plasma and rectum. Ex vivo antiviral activity of cervicovaginal lavage (CVL) was also assessed. After a single dose, RPV concentrations peaked at days 6-8 and were present in plasma and genital-tract fluid to day 84. Vaginal and male rectal tissue levels matched those in plasma. At the 1,200 mg dose, CVL showed greater antiviral activity, above baseline, at days 28 and 56. All doses were well tolerated. All doses gave prolonged plasma and genital-tract rilpivirine exposure. PK and viral inhibition of repeated doses will be important in further dose selection.

Differential effects on visual and spatial recognition memory of a novel hormone therapy regimen of estrogen alone or combined with progesterone in older surgically menopausal monkeys.

Building upon our initial studies in young adult surgically menopausal monkeys, this study examined the effects of a novel schedule of administration of estradiol therapy alone, or in combination with progesterone, on visual and spatial recognition memory in older monkeys. Monkeys were preoperatively trained on a delayed matching-to-sample task and a delayed response task. At the time of ovariectomy, monkeys began their hormonal treatments and were cognitively assessed at 2, 12 and 24 weeks following treatment initiation. A schedule of hormone administration was used that closely modeled the normal fluctuations of hormones during the course of a normal primate menstrual cycle. Monkeys receiving placebo had lower levels of accuracy than monkeys receiving estrogen therapies on the delayed matching-to-sample task that were not apparent until 12 weeks following initiation of therapy and were no longer detected at the 24-week assessment. There was no effect of hormone therapy on accuracy in the delayed response task at any of the postoperative assessments. In both tasks, monkeys treated with estrogen plus progesterone had longer choice response latencies, especially on trials in which they made errors; however these effects did not influence accuracy measures in these animals. Our findings indicate that visual recognition ability may be more sensitive than spatial recognition memory to this novel hormone therapy regimen, that treatment with estradiol plus progesterone was equivalent to that of estradiol alone, and that neither therapy had significant negative impact on memory profiles.

Pharmacokinetics and hemodynamic effects of single oral doses of thalidomide in asymptomatic human immunodeficiency virus-infected subjects.

Thalidomide (alpha-N-phthalimidoglutarimide), a potent inhibitor of tumor necrosis factor alpha (TNF-alpha), is proving to be a promising drug in the treatment of a number of inflammatory, autoimmune, and HIV-associated disorders. The pharmacokinetics and hemodynamic effects of two single oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized, two-period crossover design, in a group of asymptomatic, male HIV-seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one-compartment model with first-order absorption and elimination processes. The drug was rapidly absorbed, with a mean absorption half-life of 0.95 hr (range, 0.16-2.49 hr) and 1.19 hr (range, 0.33-3.53 hr) after 100- and 200-mg doses, respectively. The corresponding mean Cmax values were 1.15+/-0.24 microg/ml (100 mg) and 1.92+/-0.47 microg/ml (200 mg; p<0.001), which were achieved (Tmax) at 2.5+/-1.5 h and 3.3+/-1.4 hr, respectively. Plasma concentrations of thalidomide declined thereafter, in a log-linear manner, with elimination half-lives of 4.6+/-1.2 hr (100 mg) and 5.3+/-2.2 hr (200 mg). The apparent volumes of distribution (Vdss/F) were 69.9+/-15.6 liters (100 mg) and 82.7+/-34.9 liters (200 mg) while total body clearances (Cl/F) were 10.4+/-2.1 and 10.8+/-1.7 liters/hr, respectively. Significant dose-dependent decreases in supine systolic and diastolic blood pressures were seen for up to 2 hr postdosing; somnolence, headache, dizziness, and confusion were also reported more frequently at the higher dose of thalidomide.

Pharmacokinetics and absolute bioavailability of oral foscarnet in human immunodeficiency virus-seropositive patients.

The pharmacokinetics, absolute bioavailability, accumulation, and tolerability over 8 days of an oral formulation of foscarnet (90 mg/kg of body weight once daily [QD] [n = 6], 90 mg/kg twice daily [BID] [n = 6], and 180 mg/kg QD [n = 31) were investigated in 15 asymptomatic, human immunodeficiency virus-seropositive male patients free of active cytomegalovirus infection and with normal upper gastrointestinal function. Peak plasma drug concentrations were (mean +/- standard deviation) 46.4 +/- 10.8 microM (90 mg/kg QD), 45.7 +/- 6.9 microM (90 mg/ kg BID), and 64.9 +/- 31.7 microM (180 mg/kg QD) on day 1 and rose to 86.2 +/- 35.8, 78.7 +/- 35.2, and 86.4 +/- 25.0 microM, respectively, on day 8. The mean peak concentration in plasma following the intravenous administration of foscarnet (90 mg/kg) was 887.3 +/- 102.7 microM (n = 13). The terminal half-life in plasma remained unchanged, averaging 5.5 +/- 2.2 h on day 1 (n = 15) and 6.6 +/- 1.9 h on day 8 (n = 13), whereas it was 5.7 +/- 0.7 h following intravenous dosing. Oral bioavailabilities were 9.1% +/- 2.2% (90 mg/kg QD), 9.5% +/- 1.7% (90 mg/kg BID), and 7.6% +/- 3.7% (180 mg/kg QD); the accumulation ratios on the 8th day of dosing were 2.1 +/- 1.1, 1.8 +/- 0.4, and 1.7 +/- 0.7, respectively. The overall 24-h urinary excretion of oral foscarnet averaged 7.8% +/- 2.6% (day 1) and 13.4% +/- 6.0% (day 8), whereas it was 95.0% +/- 4.9% after intravenous dosing. The glomerular filtration rate and creatinine clearance remained constant, and the mean 24-h renal clearances of foscarnet for the entire study group were 96 +/- 18 ml/min (day 1), 88 +/- 13 ml/min (day 8), and 103 +/- 16 ml/min after intravenous dosing. Adverse effects were largely confined to gastrointestinal disturbances, with all subjects experiencing diarrhea that was dose dependent in its severity. The results suggest that the formulation studied would require significant improvement with respect to tolerability and bioavailability to gain clinical acceptance.

Renal excretion and pharmacokinetics of foscarnet in HIV sero-positive patients: effect of probenecid pretreatment.

AIMS: The present study was undertaken to test whether the anti-viral agent foscarnet undergoes significant tubular secretion, by using probenecid, an inhibitor of the organic acid secretory pathway in the proximal segment of the nephron. METHODS: The pharmacokinetics and renal excretion of foscarnet (90 mg kg-1 infused over 2 h) have been investigated, in the absence and presence of probenecid pretreatment (1 g twice daily for 3 days) in a group of 10 HIV seropositive patients. RESULTS: Mean (+/-s.d.) peak plasma concentrations were 904 +/- 65 microM (foscarnet) and 862 +/- 97 microM (foscarnet+probenecid) whilst the plasma AUC values were 3326 +/- 451 microM h and 3133 +/- 476 microM h respectively. Terminal elimination half-life remained unchanged at 5.6 +/- 0.7 h and the respective volumes of distribution at steady state were 23 +/- 31 (foscarnet) and 25 +/- 31 (foscarnet+probenecid). Mean total body clearance was 110 +/- 17 ml min-1 (foscarnet) and 113 +/- 13 ml min-1 (foscarnet+probenecid) and the corresponding renal clearances of foscarnet were 102 +/- 5 ml min-1 and 105 +/- 5 ml min-1 respectively. There were no significant differences in the total amount of foscarnet excreted by the kidney with 95 +/- 5% (foscarnet) and 91 +/- 6% (foscarnet+probenecid) of the intravenous dose excreted within 24 h. Glomerular filtration rates at 109 +/- 12 ml min-1 (foscarnet) and 100 +/- 13 ml min-1 (foscarnet+probenecid) and respective creatinine clearances at 120 +/- 15 and 119 +/- 10 ml min-1 remained unchanged throughout the study. CONCLUSIONS: The study shows that foscarnet is not transported via the probenecid-sensitive organic acid secretory pathway in the proximal tubule; the renal elimination of foscarnet is via glomerular filtration.