Influence of single- and multiple-dose omeprazole treatment on nifedipine pharmacokinetics and effects in healthy subjects

Summary The effects of single dose (20 mg) and short-term (20 mg/day for 8 days) oral treatment with omeprazole on the pharmacokinetics and effects of oral nifedipine (10 mg capsule) and on gastric pH have been investigated in a randomized, double-blind, placebo-controlled cross-over study in 10 non-smoking healthy male subjects.The single dose of omeprazole had no significant effect on any pharmacokinetic parameter of nifedipine, nor on gastric pH, or blood pressure or heart rate.Short-term omeprazole treatment increased the AUC of nifedipine by 26% (95% confidence interval 9–46%), but all other pharmacokinetic parameters of nifedipine, including elimination half-life, C_max, t_max, and recovery of the main urinary metabolite, were not significantly changed. The median gastric pH during the absorption phase of nifedipine was increased by short-term omeprazole (pH 4.2) compared to placebo treatment (pH 1.4). Blood pressure and heart rate did not differ between treatments.The interaction between nifedipine and omeprazole is not likely to be of major clinical relevance.     

Rizatriptan, a novel 5-HT1B/1D agonist for migraine: single- and multiple-dose tolerability and pharmacokinetics in healthy subjects

Rizatriptan is a novel 5-HT1D/1B agonist for relief of migraine headache. The pharmacokinetics, metabolite profiles, and tolerability of rizatriptan were examined in a multiple-dose study in healthy subjects. Rizatriptan (N = 24) (or placebo, N = 12) was administered as a single 10 mg dose, followed 48 hours later by administration of one 10 mg dose every 2 hours for three doses on 4 consecutive days, corresponding to the maximum daily dose for a migraine attack. The AUC of rizatriptan and its active N-monodesmethyl metabolite after three 10 mg doses was approximately threefold greater than the plasma concentrations following a single 10 mg dose. Metabolite profiles were similar after single and multiple doses. Adverse events during rizatriptan were mild and transient; similar events occurred during placebo, with a somewhat reduced incidence. Diastolic blood pressure tended to increase compared with placebo (approximately 5 mmHg), particularly on the first multiple-dose day (p < .01 vs. placebo). In conclusion, rizatriptan is well tolerated by healthy subjects during multiple-dose administration, with no unexpected accumulation of drug in plasma.     

A single- and multiple-dose study to characterize the pharmacokinetics,safety, and tolerability of ceftolozane/tazobactam in healthy Chinese participants

Ceftolozane/tazobactam (C/T) is approved in several countries to treat complicated urinary tract infections, complicated intra-abdominal infections, and nosocomial pneumonia. There is a paucity of pharmacokinetics and safety data for C/T in Chinese participants. This study evaluated the pharmacokinetics, safety, and tolerability of C/T in 12 healthy Chinese participants after three single administrations of increasing doses (0.75 g, 1.5 g, and 3 g) and multiple administrations of 1.5 g C/T every 8 h for 3 days. After single doses, maximum concentrations of ceftolozane and tazobactam were reached by the end of the 1-h infusion and declined in a biphasic manner thereafter, with mean half-lives of 1.9–2.2 h and 0.74–0.95 h, respectively. Volume of distribution (V_d) and renal clearance (CL) were consistent across the three single-dose levels for ceftolozane (V_d, 15.8–19.5 L; CL, 5.68–6.09 L/h) and tazobactam (V_d, 23.3–28.6 L; CL, 20.8–23.5 L/h). Area under the concentration–time curve (AUC) extrapolated to infinity (ceftolozane, 88.1–328 h?μg/mL; tazobactam, 10.7–48.0 h?μg/mL) increased in a dose-dependent manner. After multiple doses over 3 days, AUC from time 0 to 8 h, and concentration at the end of infusion were similar to single-dose measurements (geometric mean ratios, 0.87–1.01 for both drugs). C/T was well tolerated, with no serious adverse events or discontinuations reported; all adverse events were mild. The pharmacokinetics and safety/tolerability of C/T in healthy Chinese participants was comparable to that in previous studies in other populations, supporting the use of C/T for the treatment of Chinese patients.     

Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers

Nonsense (premature stop codon) mutations are causative in 5% to 15% of patients with monogenetic inherited disorders. PTC124, a 284-Dalton 1,2,4-oxadiazole, promotes ribosomal readthrough of premature stop codons in mRNA and offers therapeutic potential for multiple genetic diseases. The authors conducted 2 phase I studies of PTC124 in 62 healthy adult volunteers. The initial, single-dose study evaluated doses of 3 to 200 mg/kg and assessed fed-fasting status on pharmacokinetics following a dose of 50 mg/kg. The subsequent multiple-dose study evaluated doses from 10 to 50 mg/kg/dose twice per day (bid) for up to 14 days. PTC124 administered orally as a liquid suspension was palatable and well tolerated through single doses of 100 mg/kg. At 150 and 200 mg/kg, PTC124 induced mild headache, dizziness, and gastrointestinal events. With repeated doses through 50 mg/kg/dose bid, reversible transaminase elevations <2 times the upper limit of normal were sometimes observed. Immunoblot analyses of peripheral blood mononuclear cell extracts revealed no protein elongation due to nonspecific ribosomal readthrough of normal stop codons. PTC124 plasma concentrations exceeding the 2- to 10-microg/mL values associated with activity in preclinical genetic disease models were safely achieved. No sex-related differences in pharmacokinetics were seen. No drug accumulation with repeated dosing was apparent. Diurnal variation was observed, with greater PTC124 exposures after evening doses. PTC124 excretion in the urine was <2%. PTC124 pharmacokinetics were described by a 1-compartment model. Collectively, the data support initiation of phase II studies of PTC124 in patients with nonsense mutation-mediated cystic fibrosis and Duchenne muscular dystrophy.     

Safety,tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects

Safety and pharmacokinetics (PK) of the antiparasitic drug ivermectin, administered in higher and/or more frequent doses than currently approved for human use, were evaluated in a double-blind, placebo-controlled, dose escalation study. Subjects (n = 68) were assigned to one of four panels (3:1, ivermectin/placebo): 30 or 60 mg (three times a week) or 90 or 120 mg (single dose). The 30 mg panel (range: 34 7-594 microg/kg) also received a single dose with food after a 1-week washout. Safety assessments addressed both known ivermectin CNS effects and general toxicity. The primary safety endpoint was mydriasis, accurately quantitated by pupillometry. Ivermectin was generally well tolerated, with no indication of associated CNS toxicity for doses up to 10 times the highest FDA-approved dose of 200 microg/kg. All dose regimens had a mydriatic effect similar to placebo. Adverse experiences were similar between ivermectin and placebo and did not increase with dose. Following single doses of 30 to 120 mg, AUC and Cmax were generally dose proportional, with t(max) approximately 4 hours and t1/2 approximately 18 hours. The geometric mean AUC of 30 mg ivermectin was 2.6 times higher when administered with food. Geometric mean AUC ratios (day 7/day 1) were 1.24 and 1.40 for the 30 and 60 mg doses, respectively, indicating that the accumulation of ivermectin given every fourth day is minimal. This study demonstrated that ivermectin is generally well tolerated at these higher doses and more frequent regimens.     

Safety, tolerability, and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects

Dexpramipexole (KNS-760704; [6R]-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) is a novel synthetic amino-benzothiazole in development for the treatment of amyotrophic lateral sclerosis (ALS). Preclinical studies have shown that dexpramipexole is neuroprotective in vitro and in vivo, is highly orally bioavailable and water soluble, and rapidly achieves and maintains high central nervous system concentrations relative to plasma. Two phase 1 clinical studies were conducted to assess the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of dexpramipexole in 54 healthy male and female adults. The effect of food on the single-dose PK of dexpramipexole was also evaluated. Single doses (50 mg, 150 mg, or 300 mg) and multiple doses (50 mg twice daily, 100 mg twice daily, or 150 mg twice daily) of dexpramipexole over 4.5 days were safe and well tolerated. Dexpramipexole was rapidly absorbed, with time to maximum plasma concentration ranging from 1.8 to 2.6 hours and half-life ranging from 6.4 to 8.1 hours under fasted conditions, and was mostly eliminated in urine as unchanged parent drug (84%-90% of dose). Food had no effect on the single-dose PK of dexpramipexole. These findings support the ongoing development of dexpramipexole for the treatment of ALS and further evaluation of the compound's therapeutic potential in other neurodegenerative diseases.     

Single- and multiple-dose pharmacokinetics of nufenoxole in healthy human subjects

1. In 12 healthy subjects, after single doses of 20, 40 and 80 mg of nufenoxole, mean peak plasma drug concentrations of 400, 815 and 1463 ng/ml were reached at 2.2, 2.5 and 2.5 h respectively. 2. Nufenoxole was absorbed with an apparent half-life of less than one hour at all three doses. Nufenoxole concentrations declined biphasically after the peak, with an initial and terminal half-life of four to five hours and about 27 h respectively. These half-lives were independent of the administered dose. 3. AUC and Cmax increased with increasing dose, but AUC did not increase proportionately to dose, due to a lower value for 80 mg than expected, possibly reflecting reduced absorption. 4. Observed nufenoxole concentrations, in another 12 healthy subjects receiving single, daily 80 mg oral doses of nufenoxole for eight days, were in excellent agreement with those predicted from single-dose pharmacokinetics.     

Pharmacokinetics, safety and tolerance of single- and multiple-dose adefovir dipivoxil in healthy Chinese subjects

AIMS: To assess the pharmacokinetics, safety and tolerance of single- and multiple-dose adefovir dipivoxil (ADV) in healthy Chinese subjects. METHODS: Forty-two healthy subjects were randomized into 5, 10, 20, 40 and 60-mg dose groups for safety assessment. Nine and 10 healthy males were enrolled for a single-dose pharmacokinetic profile and assessment of the effect of food on the pharmacokinetics of adefovir (PMEA), respectively. Another 10 healthy subjects were enrolled for a multiple-dose safety assessment and pharmacokinetic profile. Safety and tolerance were evaluated by monitoring adverse events and laboratory parameters, and pharmacokinetics were assessed by determining PMEA concentrations with a validated LC-MS/MS method. RESULTS: No serious adverse events occurred. The pharmacokinetic parameters of PMEA following ADV 10, 20 and 40 mg were: geometric mean [95% confidence interval (CI)] for AUC(0-24 h) 227 (205, 253), 423 (361, 506) and 686 (585, 828) microg l(-1) h, C(max) 23.0 (20.7, 27.3), 47.4 (42.8, 53.2) and 83.6 (72.6, 97.4) microg l(-1), arithmetic mean (95% CI) for t(1/2) 6.8 (6.3, 7.3), 7.4 (6.7, 8.1) and 7.7 (6.5, 8.9) h, median value (range) for t(max) 1.00 (1.00-2.00), 0.75 (0.75-2.50) and 1.00 (0.75-2.00) h, respectively. The steady-state pharmacokinetics parameters were similar to those following a single dose. The AUC of PMEA was unaffected by food. CONCLUSION: ADV is safe and well tolerated in healthy Chinese subjects. The mean C(max) of PMEA is proportional to dose, but the linearity of AUC needs further study. There is no accumulation following multiple doses of ADV and the extent of absorption of PMEA is unaffected by food.     

Clinical trial: single- and multiple-dose pharmacokinetics of polyethylene glycol (PEG-3350) in healthy young and elderly subjects

Background The pharmacokinetics of polyethylene glycol 3350 (PEG‐3350) have not been fully described because of lack of a sufficiently sensitive analytical method. Aim To describe the pharmacokinetics of PEG‐3350 in humans. Methods A highly sensitive, high performance liquid chromatography with mass spectrometry (HPLC/MS/MS) method was developed for PEG‐3350 in urine, plasma and faeces with quantification limits of 30 ng/mL, 100 ng/mL and 500 μg/g respectively. Noncompartmental pharmacokinetics methods were used and the effects of gender, age, renal status and dosing frequency were examined after the oral administration of 17 g to healthy volunteers. Results Peak PEG‐3350 plasma concentrations occurred at 2–4 h and declined to nonquantifiable levels usually within 18 h after single and multiple doses, with a half‐life of about 4–6 h. Steady state was reached within 5 days of dosing. Mean urinary excretion of the administered dose ranged from 0.19% to 0.25%. Age, gender or mild kidney impairment did not alter the pharmacokinetics of PEG‐3350. Mean faecal excretion of the administered dose was 93% in young subjects. Conclusions For the first time, a highly sensitive assay allowed comprehensive pharmacokinetics studies of PEG‐3350 in humans. These studies confirmed that orally administered PEG‐3350 is minimally absorbed, rapidly excreted and primarily eliminated via faeces.     

Safety, tolerability and pharmacokinetics of escalating doses of NXY-059 in healthy young and elderly subjects

OBJECTIVE: NXY-059 is a novel, free-radical trapping, neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischaemic stroke. This study evaluated the safety, tolerability and pharmacokinetics of NXY-059 in the unbound steady-state plasma concentration (Cu(ss)) exposure range of 50-300 micromol/L in healthy young and elderly subjects. RESEARCH DESIGN AND METHODS: The primary objective of this two-centre, randomised, double-blind, placebo-controlled, dose-escalating study was to investigate the safety and tolerability, including renal function parameters and vasoirritative effects, of 8-h and 72-h intravenous infusions of NXY-059 in healthy young (20-45 years) and elderly (55-75 years) male and female subjects. The secondary objective of the study was to evaluate the pharmacokinetics of 8-h and 72-h intravenous infusions of NXY-059 in these subjects, using blood and urine samples taken during and after NXY-059 infusion as well as the doses administered. RESULTS: Of the 104 healthy volunteers who participated in the study, 72 were young and 32 were elderly. The type and incidence of adverse events in NXY-059 and placebo subjects were similar, although headache was more common in the NXY-059 group. Renal function was not altered in either group. Thrombophlebitis was reported in two elderly subjects: one receiving NXY-059 and one receiving placebo. A proportional relationship between AUC and dose for the 8-h and 72-h infusions was observed, and clearance did not change with dose. CONCLUSIONS: NXY-059 was well tolerated at all plasma concentrations tested in both the young and elderly subjects, and no safety concerns were raised. Linear pharmacokinetics were observed following 8-h and 72-h infusions of NXY-059 at doses resulting in an average Cu(ss) in the 52-317 micromol/L range.     

Pharmacokinetics and tolerability of cinitapride in healthy Chinese volunteers: a randomized,open-label,single- and multiple-dose study

1. Cinitapride (CIN) is a drug for functional dyspepsia. The purpose of the study was to investigate the pharmacokinetics and tolerability of CIN in healthy Chinese volunteers.

2. A randomized, open-label, single- and multiple-dose study was conducted in 12 healthy volunteers. Three different doses of CIN (1, 2, 4 tablets) were given to six groups in the single-dose study, and one tablet (1?mg) of CIN was administered three times a day in the multiple-dose study. Blood samples were collected at predetermined time intervals after CIN dosing and analyzed by LC-MS/MS.

3. Eleven volunteers completed the study. After single dose, the C_max and AUC of plasma increased approximately linearly with dosage; no statistically significant differences were found in pharmacokinetic parameters between three dose groups. After multiple doses, there was no significant change in T_max and t_1/2 compared with the results from the single dose. After repeated doses, AUC_0-t and AUC_0-∞ were increased, while CLz/F slightly decreased. And no differences between male and female.

4. The pharmacokinetic parameters of this study were consistent with study results of non-Chinese subjects. Good tolerability was demonstrated in both single- and multiple-dose studies with dosage range from 1 to 4?mg in healthy Chinese subjects.

     

安纳拉唑钠肠溶片在健康受试者中多次给药的药代动力学、药效学和耐受性研究

目的 研究安纳拉唑钠肠溶片60,80或100 mg连续给药在健康受试者中的药代动力学、药效学和安全耐受性.方法 采用随机、双盲双模拟、安慰剂和阳性药对照的试验设计,共计纳入45例中国健康受试者.各剂量组中10例受试者服用试验药物(安纳拉唑钠肠溶片60,80或100 mg),2例受试者服用阳性对照药(雷贝拉唑钠肠溶片20...     

Pharmacokinetics of flunitrazepam following single- and multiple-dose oral administration to healthy human subjects

Healthy human subjects received single and multiple oral doses of flunitrazepam. Absorption and disposition were first order and reproducible from administration to administration. The oral doses were virtually completely available to the liver, and elimination from the body occurred entirely via metabolism. Assuming the liver to be the sole eliminating organ, hepatic blood clearance and extraction ratio were approximately 0.235 liter/hr/kg and 0.154, respectively. Steady-state blood volume of distribution averaged 3.76 liters/kg in the single-dose studies. Terminal exponential half-lives from the single- and multiple-dose studies (different subjects) averaged 13.5 and 19.2 hr, respectively, these differences were not due to clearance changes but were entirely attributable to variations in volumes of distribution.     

Safety, tolerability and pharmacokinetics of udenafil, a novel PDE-5 inhibitor, in healthy young Korean subjects

AIM

To evaluate the safety, tolerability and pharmacokinetics (PK) of udenafil, a novel phosphodiesterase type 5 inhibitor.

METHODS

A double-blind, randomized, placebo-controlled, dose-rising, parallel-group, single- and multiple-dose study was conducted in healthy Korean subjects. The subjects were allocated to single-dose groups of 25, 50, 100, 200 or 300 mg (eight subjects in each dose group, including two placebos), or to multiple-dose groups of 100 or 200 mg (once-daily dosing for 7 days; nine subjects in each dose group, including three placebos). Serial samples of blood and urine were collected after oral administration and the drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Safety and tolerability were evaluated by monitoring clinical laboratory parameters and adverse events.

RESULTS

Udenafil reached peak plasma concentrations at 0.8–1.3 h, and then declined mono-exponentially with a terminal half-life of 7.3–12.1 h in the single-dose study. The area under the time–concentration curves (AUC) and maximum plasma concentrations (C_max) increased supraproportionally with increasing dose in the single-dose study. During multiple dosing, a steady state was reached at 5 days and little accumulation occurred after repeated dosing for 7 days. Udenafil was generally well tolerated in these healthy subjects, and no serious adverse events occurred.

CONCLUSIONS

Udenafil was safe and well tolerated in healthy volunteers. The AUC and C_max of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The phosphodiesterase (PDE) type 5 inhibitor is a widely used agent that facilitates penile erection.
• Udenafil is newly developed as a PDE-5 inhibitor.

WHAT THIS STUDY ADDS

• This is the first study to determine the safety, tolerability and pharmacokinetics of udenafil in healthy subjects.
• Udenafil was safe and well tolerated in healthy Korean subjects.
• The AUC and C_max of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.

     

Safety,tolerability and pharmacokinetics of escalating doses of NXY-059 in healthy young and elderly subjects*

ABSTRACT

Objective: NXY-059 is a novel, free-radical trapping, neuroprotectant that reduces infarct size and preserves brain function in animal models of acute ischaemic stroke. This study evaluated the safety, tolerability and pharmacokinetics of NXY-059 in the unbound steady-state plasma concentration (Cuss) exposure range of 50-300 μmol/L in healthy young and elderly subjects.

Research design and methods: The primary objective of this two-centre, randomised, double-blind, placebo-controlled, dose-escalating study was to investigate the safety and tolerability, including renal function parameters and vasoirritative effects, of 8‐h and 72‐h intravenous infusions of NXY‐059 in healthy young (20–45 years) and elderly (55–75 years) male and female subjects. The secondary objective of the study was to evaluate the pharmacokinetics of 8‐h and 72‐h intravenous infusions of NXY‐059 in these subjects, using blood and urine samples taken during and after NXY‐059 infusion as well as the doses administered.

Results: Of the 104 healthy volunteers who participated in the study, 72 were young and 32 were elderly. The type and incidence of adverse events in NXY‐059 and placebo subjects were similar, although headache was more common in the NXY‐059 group. Renal function was not altered in either group. Thrombophlebitis was reported in two elderly subjects: one receiving NXY-059 and one receiving placebo. A proportional relationship between AUC and dose for the 8‐h and 72‐h infusions was observed, and clearance did not change with dose.

Conclusions: NXY-059 was well tolerated at all plasma concentrations tested in both the young and elderly subjects, and no safety concerns were raised. Linear pharmacokinetics were observed following 8‐h and 72‐h infusions of NXY‐059 at doses resulting in an average Cu_ss in the 52–317?µmol/L range.     

Methaqualone pharmacokinetics after single- and multiple-dose administration in man

Serum levels of methaqualone (MTQ) were determined in eight unfasted subjects following single- and multiple-dose administration of 1×300 mgtablet over a 28-day period. Data were analyzed by a two-compartment open model. Following a fairly rapid absorptive phase (K _a =0.82±0.32 hr^–1),the serum elimination curve was biexponential, consisting of a phase predominantly due to distribution (=0.97±0.55 hr^–1)and a phase predominantly due to elimination (=0.036±0.004 hr^–1).A steady-state MTQ serum concentration profile was observed within the first week. There were no significant changes in the kinetics of absorption, distribution, or elimination over the 28-day period of drug administration. Urinary D-glucaric acid excretion, which increased two-to threefold after the first week of MTQ dosing, returned to normal levels when the drug was discontinued. The significance of the pharmacokinetic parameters in relation to bioavailability and biological disposition of single and multiple dose MTQ administration is discussed.     

Safety, tolerability and pharmacokinetics of higher-dose mizoribine in healthy male volunteers

AIMS: Mizoribine is an oral immunosuppressive agent approved in several countries for prevention of rejection in renal transplantation. Its therapeutic window is based on trough concentrations staying at > or =0.5 but <3 microg ml(-1). It has been postulated that as renal function returns to normal, higher doses may be needed to maintain efficacy than the current clinical dosage of 2-5 mg kg(-1) day(-1). The safety, tolerability and pharmacokinetics from two clinical trials of higher-dose mizoribine treatments in healthy male volunteers are presented. METHODS: Forty-eight healthy White male nonsmokers participated in two randomized, double-blind, placebo-controlled trials: 32 in a single-dose study (3, 6, 9 and 12 mg kg(-1)) and 16 in a multiple-dose study [6 mg kg(-1) day(-1) once daily for 5 days or twice daily (12 mg kg(-1) day(-1)) for 7 days]. Standard assessments of safety, tolerability and pharmacokinetics were performed. RESULTS: The safety profiles of both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg kg(-1) day(-1)) in the multiple-dose study. Orally administered mizoribine reached peak concentrations within 2-3 h and was eliminated mostly via the kidney (65-100% of dose) with a 3-h half-life. Only the 12 mg kg(-1) day(-1) group achieved trough concentrations that were within the therapeutic window. Conclusions Based on the favourable safety profile and current pharmacokinetic information, a new starting dose in the 6-12 mg kg(-1) day(-1) range is recommended in the up to 3 months acute phase following transplantation, with dose reduction recommended only if the function of the transplanted kidney is impaired.     

Pharmacokinetics of flunitrazepam following single- and multiple-dose oral administration to healthy human subjects.

Healthy human subjects received single and multiple oral doses of flunitrazepam. Absorption and disposition were first order and reproducible from administration. The oral doses were virtually completely available to the liver, and elimination from the body occurred entirely via metabolism. Assuming the liver to be the sole eliminating organ, hepatic blood clearance and extraction ratio were approximately 0.235 liter/hr/kg and 0.154, respectively. Steady-state blood volume of distribution averaged 3.76 liters/kg in the single-dose studies. Terminal exponential half-lives from the single- and multiple-dose studies (different subjects) averaged 13.5 and 19.2 hr, respectively; these differences were not due to clearance changes but were entirely attributable to variations in volumes of distribution.