Randomized, Double-Blind, Controlled Study to Evaluate Safety and Pharmacokinetics of Single Ascending Doses of ASP5354, an Investigational Imaging Product, in Healthy Adult Volunteers.

Intraoperative ureter identification helps reduce the risk of ureteral injury. Currently, no suitable agents for real-time ureter visualization are approved. ASP5354 (TK-1) is a novel indocyanine green derivative. In this first-in-human phase 1, double-blind, sequential ascending-dose study, urethral catheters were placed in 6 healthy volunteers who were randomized to single-dose, intravenous ASP5354 0.1 mg (n = 4) or placebo (n = 2). Sequential dose escalations to 0.5-, 2-, 8-, and 24-mg ASP5354 in new cohorts were contingent upon Dose-Escalation Committee approval after review of pharmacokinetic (PK) and safety data. Blood and urine samples were collected over 24 hours following dose administration. Objectives were to assess the safety/tolerability and PK of ASP5354. Treatment-emergent adverse events (TEAEs) were reported in 3 (15%) and 2 (20%) participants in the ASP5354 and placebo groups, respectively. In the former, there were 6 TEAEs (5/6 grade 1-2). One ASP5354 participant experienced grade 3 pyelonephritis, attributed to the catheter. No TEAEs were related to ASP5354. Mean plasma terminal elimination half-life ranged from 2.1 to 3.6 hours, with near complete urinary excretion of unchanged ASP5354 within 24 hours after administration. Linear and dose-proportional PK were observed. These results support further evaluation of ASP5354 at doses up to 24 mg for intraoperative near-infrared fluorescence ureter visualization.

Pharmacokinetic effects of simultaneous administration of single-dose gabapentin 500 mg and zolpidem tartrate 10 mg in healthy volunteers: a randomized, open-label, crossover trial.

OBJECTIVE: Gabapentin is being investigated as a potential treatment for occasional disturbed sleep. This study assessed the pharmacokinetics and tolerability of gabapentin 500 mg and the commonly prescribed sedative/hypnotic zolpidem tartrate 10 mg, administered separately and in combination. METHODS: Forty healthy participants (19 male, 21 female) were randomized into this three-period crossover study [mean (range) age 34.1 (18-45) years, weight 68.3 (51.4-92.7) kg; 60 % white]. Participants were dosed with gabapentin alone (n = 39), zolpidem tartrate alone (n = 38), and the combination (gabapentin + zolpidem) (n = 38) over three treatment periods, which were separated by ≥7 days. Blood samples were collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24 and 36 h post-dose. Plasma concentrations of each drug were assayed using validated methods. Pharmacokinetic parameters were estimated from plasma concentration-time data using standard non-compartmental methods. RESULTS: For gabapentin + zolpidem combination versus gabapentin alone, mean pharmacokinetic parameters were peak plasma concentration (C max) 4.61 versus 4.72 µg/mL, time to Cmax (t max) 4.63 versus 3.64 h and the area under plasma concentration-time curve extrapolated to infinity (AUC0-∞) 53.4 versus 51.0 µg h/mL. For the combination versus zolpidem alone, mean pharmacokinetic parameters were C max 154 versus 138 ng/mL, t max 1.45 versus 1.84 h and AUC0-∞ 912 versus 854 ng h/mL. The 90 % confidence intervals for C max (rate of absorption) and AUC0-∞ (extent of absorption) comparing the combination versus single drug administration fell within the 80-125 % range accepted for bioequivalence. All treatments were well tolerated. CONCLUSION: The pharmacokinetics of gabapentin 500 mg and zolpidem tartrate 10 mg are unaffected when both drugs are taken simultaneously, compared with each drug taken alone.

Helicase-primase inhibitor pritelivir for HSV-2 infection.

BACKGROUND: Pritelivir, an inhibitor of the viral helicase-primase complex, exhibits antiviral activity in vitro and in animal models of herpes simplex virus (HSV) infection. We tested the efficacy and safety of pritelivir in otherwise healthy persons with genital HSV-2 infection. METHODS: We randomly assigned 156 HSV-2-positive persons with a history of genital herpes to receive one of four doses of oral pritelivir (5, 25, or 75 mg daily, or 400 mg weekly) or placebo for 28 days. Participants obtained daily swabs from the genital area for HSV-2 testing, which was performed with a polymerase-chain-reaction assay. Participants also maintained a diary of genital signs and symptoms. The primary end point was the rate of genital HSV shedding. RESULTS: HSV shedding among placebo recipients was detected on 16.6% of days; shedding among pritelivir recipients was detected on 18.2% of days among those receiving 5 mg daily, 9.3% of days among those receiving 25 mg daily, 2.1% of days among those receiving 75 mg daily, and 5.3% of days among those receiving 400 mg weekly. The relative risk of viral shedding with pritelivir, as compared with placebo, was 1.11 (95% confidence interval [CI], 0.65 to 1.87) with the 5-mg daily dose, 0.57 (95% CI, 0.31 to 1.03) with the 25-mg daily dose, 0.13 (95% CI, 0.04 to 0.38) with the 75-mg daily dose, and 0.32 (95% CI, 0.17 to 0.59) with the 400-mg weekly dose. The percentage of days with genital lesions was also significantly reduced, from 9.0% in the placebo group to 1.2% in both the group receiving 75 mg of pritelivir daily (relative risk, 0.13; 95% CI, 0.02 to 0.70) and the group receiving 400 mg weekly (relative risk, 0.13; 95% CI, 0.03 to 0.52). The rate of adverse events was similar in all groups. CONCLUSIONS: Pritelivir reduced the rates of genital HSV shedding and days with lesions in a dose-dependent manner in otherwise healthy men and women with genital herpes. (Funded by AiCuris; ClinicalTrials.gov number, NCT01047540.).

Effects of rifampin and ketoconazole on the pharmacokinetics of nilotinib in healthy participants.

Nilotinib (Tasigna), an orally bioavailable second-generation BCR-ABL tyrosine kinase inhibitor, is approved for use in patients with chronic myeloid leukemia in chronic phase and accelerated phase who are resistant or intolerant to prior therapy, including imatinib. Previous in vitro studies indicated that nilotinib metabolism is primarily mediated by CYP3A4. To investigate the effect of CYP3A4 induction and inhibition on nilotinib pharmacokinetics, 2 studies were conducted in healthy volunteers prior to and following treatment with a strong inducer (rifampin) or inhibitor (ketoconazole). In the induction study, administration of rifampin 600 mg once daily for 8 days significantly increased urinary 6ß-hydroxycortisol/ cortisol ratio, from a preinduction baseline of 5.8 ± 2.7 to 18.0 ± 10.2 after 8 days of rifampin treatment, confirming an inductive effect on CYP3A4. Nilotinib oral clearance was increased by 4.8-fold, and the maximum serum concentration (C(max)) and area under the serum concentration-time curve (AUC) were decreased by 64% and 80%, respectively, in the induced state compared with baseline. In the inhibition study, ketoconazole 400 mg once daily for 6 days increased the C(max) and AUC of nilotinib by 1.8- and 3-fold, respectively, compared with nilotinib alone. These results indicate that concurrent use of strong CYP3A4 inducers or inhibitors may necessitate dosage adjustments of nilotinib and should be avoided when possible.

Effect of omeprazole on the pharmacokinetics of paricalcitol in healthy subjects.

Paricalcitol capsules are indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease (CKD). Proton pump inhibitors are prescribed to CKD patients to treat gastroesophageal reflux. This was a single dose, crossover study evaluating the effect of omeprazole, change in gastric pH as a result thereof, on the pharmacokinetics (PK) of paricalcitol. Twenty-six healthy subjects were administered paricalcitol capsules (16 microg) alone (regimen A), and following a single dose of OMP (40 mg) (regimen B), with a washout of at least 7 days. Plasma samples for paricalcitol concentrations were collected for 48 h post-paricalcitol dose. The plasma paricalcitol concentrations were measured using an LC-MS/MS assay (LOQ=0.02 ng/ml) and paricalcitol pharmacokinetic parameters were estimated using non-compartmental methods. The point estimates and the corresponding 90% confidence intervals for Cmax and AUC0-infinity to evaluate paricalcitol-omeprazole interaction were 1.032 [0.920-1.158] and 1.041 [0.951-1.139], respectively. No significant differences in Tmax (regimen A: 2.9 h vs regimen B: 2.6 h) or t1/2 (6.83 h vs 6.6 h) between the regimens were observed. Hence, the co-administration of omeprazole does not affect the PK of paricalcitol. Both regimens were well tolerated and no apparent differences among the regimens with respect to safety were observed.

Effect of repeated oral administrations of the oral adsorbent AST-120 on serum creatinine and other markers of renal function. A randomized controlled study in patients with chronic kidney disease.

BACKGROUND: AST-120 is an orally administered adsorbent used in Japan for prolonging time to initiation of hemodialysis and improving uremic symptoms in patients with chronic kidney disease (CKD). As AST-120 is suspected to reduce the progression of CKD by adsorbing renal toxins in the gastrointestinal tract, the objective of the current study was to determine whether binding of AST-120 to creatinine in the intestines could acutely alter creatinine balance, thereby limiting the utility of serum creatinine (sCr) as a measure of progression of renal function. Such information may be critical for the design of future studies to assess the efficacy of AST-120 in CKD patients. METHODS: Patients with CKD (n = 20) received oral doses of AST-120(3 g t.i.d.) and placebo in a two-way crossover study. Blood and urine were collected for determination of sCr, 24-hour urinary creatinine (UcrV), creatinine clearance (Ccr), and urea nitrogen clearance (URCL). Differences between treatments were assessed using an ANCOVA model. RESULTS: Following AST-120 and placebo treatments, mean sCr (1.73 and 1.79 mg/dl, respectively) and UcrV (1,264.73 and 1,286.05 mg) values were not significantly different. No significant differences were observed for Ccr and URCL. CONCLUSION: These results indicate that AST-120 has no acute impact on creatinine balance in patients with CKD. Consequently, sCr and other markers of renal function are acceptable measures for assessing changes in renal function following AST-120 treatment.

Pharmacokinetics of insulin aspart in obesity, renal impairment, or hepatic impairment.

AIMS: To assess the effects of body mass index, renal impairment (creatinine clearance), and hepatic impairment (Child-Pugh Score) on the pharmacokinetics of insulin aspart. METHODS: Pharmacokinetics of insulin aspart (injected subcutaneously in the abdomen immediately before a Boost standardized meal) were characterized in: (1) diabetic subjects with four ranges of BMI values (n = 23); (2) diabetic subjects with varying degrees of renal impairment (normal, n = 6 vs. two ranges of impairment, n = 12); and (3) nondiabetic patients with varying degrees of hepatic impairment (normal, n = 6 vs. three ranges of impairment, n = 18). RESULTS: There was no correlation between any pharmacokinetic variable and the degree of renal or hepatic impairment. Increasing obesity was associated with a decreased apparent clearance per kg body weight (beta = -0.0005, SE = 0.0001; P = 0.002), an increased t((1/2)) (beta = 3.513, SE = 1.636; P = 0.044), and an increased ln(AUC(0-360)) and ln(AUC(0-1440)) (beta = 0.030, SE = 0.013; P = 0.032 and beta = 0.039, SE = 0.0132; P = 0.006, respectively). However, obesity-related changes were smaller than individual variations in parameters. CONCLUSIONS: Renal impairment, hepatic impairment, or BMI do not affect the pharmacokinetics of insulin aspart in a clinically significant manner.

Lack of effect of moderate hepatic impairment on the pharmacokinetics of oral oseltamivir and its metabolite oseltamivir carboxylate.

AIMS: To compare the pharmacokinetics of oseltamivir and oseltamivir carboxylate in hepatically impaired patients and healthy subjects. METHODS: Hepatically impaired patients (n = 11) and healthy subjects (n = 11) were individually paired on the basis of gender, age (+/-10 years) and body weight (+/-20%) and administered a single dose of oseltamivir (75 mg). RESULTS: Oseltamivir and oseltamivir carboxylate C(max) were < or =6% and < or =19% lower, and their AUC(0,infinity) 33% higher and < or =19% lower, respectively, in hepatically impaired patients compared with healthy subjects. These changes are within the safety limits for the drug. CONCLUSIONS: The metabolism of oseltamivir is not compromised [corrected] in hepatically impaired patients. No dose adjustment is required in these patients when receiving oseltamivir.

Pharmacokinetic characterization of different dose combinations of coadministered tipranavir and ritonavir in healthy volunteers.

PURPOSE: To characterize the steady-state pharmacokinetic combination of the nonpeptidic protease inhibitor tipranavir (TPV) with ritonavir (RTV) in 95 healthy adult volunteers, a phase 1, single-center, open-label, randomized, parallel-group trial was conducted. METHOD: Participants received 250-mg self-emulsifying drug delivery system (SEDDS) capsules of TPV at doses between 250 mg and 1250 mg twice daily for 11 days, then received one or two RTV 100-mg SEDDS capsules, in addition to the TPV capsules, for the next 21 days. RESULTS: Coadministration of TPV and RTV (TPV/r) resulted in a greater than 20-fold increase in steady-state TPV trough concentrations (Cssmin) as compared with TPV at steady state alone. Mean TPV Cssmin was above a preliminary target threshold of 20 microM with all but one of the RTV-boosted doses; without boosting, none of the TPV-alone doses exceeded the threshold. The average steady-state Cssmin for TPV 500 mg and 750 mg with RTV 100 mg or 200 mg were 20 to 57 times the protein-adjusted TPV IC90R49\CCR418569) for protease inhibitor-resistant HIV-1. An erythromycin breath test, a surrogate marker for cytochrome P450 isoenzyme 3A4 activity, indicated that all TPV/r combinations given provided net inhibition of this isoenzyme. The most frequent treatment-related adverse events were mild gastrointestinal symptoms. CONCLUSION: This phase 1 study demonstrated that RTV-boosted TPV achieves concentrations that are expected to be effective in treating drug-experienced patients.