Passive transfer of neutralizing mAb KD-247 reduces plasma viral load in patients chronically infected with HIV-1.

OBJECTIVE: Neutralizing antibodies against HIV-1 such as a humanized mAb KD-247 can mediate effector functions that attack infected cells in vitro. However, the clinical efficacy of neutralizing antibodies in infected individuals remains to be determined. We evaluated the safety, tolerability and pharmacokinetics of KD-247 infusion and its effect on plasma HIV-1 RNA load and CD4 T-cell count. DESIGN AND METHODS: KD-1002 is a phase Ib, double-blind, placebo-controlled, dose-escalation study of KD-247 in asymptomatic HIV-1 seropositive individuals who did not need antiretroviral therapy. Individuals were randomized to 4, 8 or 16 mg/kg KD-247 or placebo, and received three infusions over a 2-week period. RESULTS: Patients were randomized to receive one of the three doses of KD-247 and the treatment was well tolerated. We observed a significant decrease in HIV RNA in the 8 and 16 mg/kg KD-247 cohorts, with two individuals who achieved more than 1 log reduction of HIV RNA. Two patients in the 16 mg/kg cohort had selections and/or mutations in the V3-tip region that suggested evasion of neutralization. Long-term suppression of viral load was observed in one patient despite a significant decrease in plasma concentration of KD-247, suggesting effects of the antibody other than neutralization or loss of fitness of the evading virus. CONCLUSION: The results indicate that KD-247 reduces viral load in patients with chronic HIV-1 infection and further clinical trials are warranted.

Evaluation of the pharmacodynamics of acetylsalicylic acid 81 mg with or without esomeprazole 20 mg in healthy volunteers.

BACKGROUND: The absence of a pharmacokinetic interaction between the proton pump inhibitor esomeprazole (40 mg) and acetylsalicylic acid (aspirin, ASA; 325 mg) has previously been established. OBJECTIVE: This study set out to investigate the potential for pharmacodynamic interaction between low-dose ASA and esomeprazole in healthy volunteers, by measuring ASA antiplatelet activity. STUDY DESIGN: This was a single-center, open-label, two-period, randomized crossover study. PARTICIPANTS: Healthy male and female volunteers aged 18-75 years were included. All volunteers received ASA 81 mg once daily for 5 days prior to the study (pre-screen). Subjects were eligible for inclusion if they had aspirin reactivity units (ARU, as measured by the VerifyNow ASA assay) of <550 on Day 6. INTERVENTION: After pre-screening and a washout period of at least 14 days, eligible volunteers received ASA 81 mg with or without esomeprazole 20 mg once daily for 5 days in randomized order, with a 14-day washout between treatments. MAIN OUTCOME MEASURE: The main outcome measure was the antiplatelet activity of ASA, as assessed by ARU ratio relative to baseline in the VerifyNow ASA assay; suppression of serum thromboxane B(2) (TXB(2)) was a secondary endpoint. Statistical comparisons were made using linear mixed models. RESULTS: A total of 29 volunteers (19 aged ≥50 years; 8 women; 21 men) were evaluable for pharmacodynamic analysis (per protocol). All volunteers on both treatments achieved ARU <550 at Day 6. The geometric mean ratio of Day 6 to Day 1 (baseline) platelet aggregation was 0.70 (95% confidence interval [CI] 0.68, 0.72) with ASA alone and 0.71 (95% CI 0.69, 0.74) with ASA + esomeprazole. The ratio of platelet aggregation (ASA + esomeprazole/ASA) was 1.02 (95% CI 0.99, 1.05). ASA administered alone or with esomeprazole reduced serum TXB(2) by more than 99.5%. The ratio of suppression of serum TXB(2) levels (ASA + esomeprazole/ASA) was 1.06 (95% CI 0.88, 1.29). The combination of ASA and esomeprazole was well tolerated. CONCLUSION: No pharmacodynamic interaction between low-dose ASA and esomeprazole was found with regard to platelet function. TRIAL REGISTRATION: Registered at ClinicalTrials. gov as NCT01199328.

Pharmacokinetics and safety assessments of high-dose and 4-week treatment with S-3304, a novel matrix metalloproteinase inhibitor, in healthy volunteers.

AIMS: To investigate the tolerability, safety and pharmacokinetics of S-3304 in healthy volunteers treated with high doses of S-3304 for 28 days. METHODS: Thirty-two healthy volunteers were recruited. Four male and four female subjects were allocated to one of four doses (800 mg, 1600 mg, 2400 mg and 3200 mg). At each dose six volunteers took active medication and two volunteers took placebo in a double-blind fashion. Volunteers took a single dose on days 1 and 28 for pharmacokinetic purposes, and took twice daily doses from day 3-27. The pharmacokinetics of S-3304 and its hydroxy metabolites were evaluated. Tolerance was based on subjective adverse events, clinical examination, vital signs, ECG and laboratory tests including haematology and biochemistry profiles using CTC grading. RESULTS: Doses up to 2400 mg twice daily were generally well tolerated. At 3200 mg twice daily, five volunteers including one randomized to placebo were withdrawn from treatment mainly due to alanine aminotransferase (ALT) elevation. C(max) of S-3304 on day 1, whose geometric mean and 95% confidence interval were 66.3 microg ml(-1) (48.8, 90.0) for 800 mg, 82.6 microg ml(-1) (69.3, 98.6) for 1600 mg, 89.5 microg ml(-1) (79.5, 100.7) for 2400 mg, and 110.5 microg ml(-1) (88.9, 137.7) for 3200 mg, respectively, was correlated with the log-transformed peak ALT (P < 0.0001 for male and P = 0.048 for female volunteers). CONCLUSIONS: In healthy volunteers the maximum tolerated dose of S-3304 was 2400 mg twice daily. ALT elevation was the most frequent dose-limiting factor and was correlated with C(max) on day 1.

Intraindividual and interindividual variations in the pharmacokinetics of mycophenolic acid in liver transplant patients.

The authors evaluated the intraindividual and interindividual variations in the pharmacokinetics of mycophenolic acid after oral administration of mycophenolate mofetil in 10 liver transplant patients. Mycophenolic acid and its metabolite, mycophenolic acid glucuronide, were measured in plasma and urine by high-pressure liquid chromatography. The plasma protein binding of mycophenolic acid was determined by ultrafiltration. The maximum concentration of mycophenolic acid in plasma increased significantly (P < or = .05) with time from 9.1 +/- 7.2 microg/mL (<1 week) to 36.7 +/- 15.6 microg/mL (1 month). The area under the plasma concentration versus time curve of mycophenolic acid also increased significantly with time, from 50.8 +/- 42.1 microg x h/mL to 118.0 +/- 57.6 microg x h/mL (P < or = .05). The plasma protein binding of mycophenolic acid increased from 92% to 98%, and the apparent oral clearance [CL/F] decreased from 32.9 +/- 21.4 L/h during the first study period to 9.0 +/- 4.4 L/h (P < or = .05) during the third study period. The apparent intrinsic clearance of mycophenolic acid did not change significantly over time. The ratio of the area under the curve of mycophenolic acid glucluronide to mycophenolic acid in plasma decreased with time (25.5 +/- 21.2 vs 8.0 +/- 3.3) but did not reach statistical significance. The increased binding of mycophenolic acid to plasma proteins with time after transplantation appeared to contribute to the intraindividual variation, whereas differences in the ability of the liver to metabolize mycophenolic acid between patients appear to contribute to the large interindividual variation in the pharmacokinetics of mycophenolic acid. The observations in this study support the concept of measuring the unbound concentration of mycophenolic acid to optimize immunosuppressive drug therapy with mycophenolic acid.