Multiple-dose pharmacokinetics of nilvadipine in healthy volunteers

Nilvadipine, a new antihypertensive and antianginal drug, was studied in six healthy male volunteers to evaluate its steady-state pharmacokinetics after oral dosing. The subjects were given a single dose of 4 mg, followed by 4 mg every 12 hours for six days after a washout period of more than 3 days. The pharmacokinetics of nilvadipine were well described by a linear model of triexponential equation with zero-order absorption. The steady state was reached by the fourth day of multiple dosing, with a twofold accumulation of trough plasma concentration and no accumulation of peak concentration. The mean plasma concentration at steady state was 1.0 ng/mL. The optical enantiomers of nilvadipine were also determined in the plasma. The plasma concentration of (+)-nilvadipine was about two and a half times higher than that of (-)-nilvadipine, and this ratio was unaffected by multiple dosing.     

Multiple-dose pharmacokinetics of intranasally administered IS-159 in healthy subjects.

This study was designed to investigate the multiple-dose pharmacokinetics of a range of intransal doses of IS-159, a serotonin 1B/1D receptor agonist. Intranasal doses of 1, 2, 4 and 6 mg of IS-159 were administered twice at an interval of 4 hours to 17 healthy male and female subjects in a two-way crossover study. Plasma concentrations of IS-159 were determined from blood samples taken at regular intervals up to 24 hours after the first administration during both treatment periods. IS-159 was rapidly absorbed and eliminated with a t(max) of approximately 15 min and a t(1/2) of approximately 1.6 hours. With increasing dose, the exposure increased dose-proportionally, and IS-159 pharmacokinetics appear not to be influenced by gender and food intake. The results showed dose-proportional pharmacokinetics of IS-159 in the dose range tested and a low propensity for drug accumulation.     

Multiple-dose pharmacokinetics of fesoterodine sustained-release in healthy Korean volunteers

Objective: Fesoterodine is a pro-drug of the active metabolite 5-hydroxymethyl tolterodine (5-HMT), a muscarinic receptor antagonist. This study aimed to evaluate the safety profile and pharmacokinetic characteristics of multiple oral doses of sustained-release fesoterodine (fesoterodine SR) in healthy Korean males. Methods: A randomized, double-blind, placebo-controlled, multiple-dose study with two oral doses (4 mg and 8 mg) was conducted in healthy Korean male participants. The study drug was administered once daily for 5 days. The plasma concentration of 5-HMT was measured up to 72 hours after the last drug administration. The CYP2D6 genotype was analyzed using polymerase chain reaction (PCR) methods to assess the effect of genetic polymorphisms on the pharmacokinetic parameters. Results: 20 participants completed the study. The mean (SD) areas under the plasma concentration-time curves during the dosing interval (AUCτ) of the 4 mg and 8 mg dose groups were 26.1 (8.0) and 64.2 (30.5) μga??h/ml and the mean peak concentrations (Cmax) were 2.6 (0.7) and 6.0 (2.0) μg/ml, respectively, at steady-state. The mean AUCτ and Cmax of 5-HMT increased in approximately the same proportion as the dose increased. Fesoterodine SR was well tolerated without any serious adverse events or abnormal clinical laboratory findings. Conclusion: Systemic 5-HMT exposure showed dose-proportional characteristics in the 4 mg to 8 mg dose range in healthy Korean males. Thus, 4 mg or 8 mg doses of fesoterodine SR taken once-daily were tolerable in healthy Korean males.     

Multiple-dose pharmacokinetics of cefepime in long-term hemodialysis with high-flux membranes

Objective: Among uremic patients on hemodialysis, infectious complications leading to a high incidence of morbidity and mortality are a well-documented problem. In this multi-dose study, the safety, tolerance, and pharmacokinetics of cefepime during high-flux hemodialysis were investigated and an improved dosing schedule is presented. Methods: Six long-term hemodialysis patients received 2 g cefepime i.v. at the end of hemodialysis three times per week. Results: Trough levels of cefepime were 23.3 ± 7.3 mg/l and peak serum concentrations 165.6 ± 48.7 mg/l. After 3.5 h of high-flux hemodialysis, 72.2 ± 6.4% of cefepime was eliminated. The intradialytic half-life was 1.6 ± 0.29 h and the interdialytic half-life 22.0 ± 2.14 h. Conclusion: A dosage of 2 g cefepime after each hemodialysis session achieved drug levels well above the minimal inhibitory concentration (MIC)₉₀ for most of the target pathogens. Thus, the described dosing schedule is an efficient and cost saving antmicrobial therapy for severe infections in long-term hemodialysis patients with no residual renal function. Received: 12 October 1999 / Accepted in revised from: 12 January 2000     

Multiple-dose pharmacokinetics of piperacillin and azlocillin in 12 healthy volunteers

The pharmacokinetic profile of piperacillin and azlocillin after multiple-dose administration to healthy volunteers was studied. Twelve healthy volunteers received either piperacillin 4 g (as the sodium salt) or azlocillin 4 g (as the sodium salt) as a 20-minute infusion every six hours for five doses. After a one-week washout period, subjects received identical treatment with the alternate drug. Serum and urine concentrations of piperacillin and azlocillin were measured using a reversed-phase high-performance liquid chromatographic assay, and the pharmacokinetic analysis of serum concentration-versus-time data was performed using a computerized program. A standard open-model equation for i.v. infusions was used. Mean serum concentrations of piperacillin and azlocillin after dose 5 were 344 +/- 66 micrograms/mL and 414 +/- 86 micrograms/mL, respectively. The terminal elimination half-life of azlocillin (1.1 +/- 0.2 hr) was significantly longer than that of piperacillin (0.75 +/- 0.13 hr) (p less than 0.05). Total body clearance of azlocillin (125 +/- 25 mL/min) was significantly less than that of piperacillin (226 +/- 43 mL/min) after dose 5. Azlocillin showed accumulation between the first and fifth doses. Twelve hours after administration of dose 5, 75% of azlocillin and 57% of piperacillin were excreted unchanged into the urine. In healthy volunteers, azlocillin produced higher and more prolonged serum concentrations than piperacillin after administration of equivalent i.v. doses. Further studies are needed to determine the clinical importance of these observations.     

Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children.

The disposition of antipyretic drugs is central to the understanding of their action in children. Accordingly, the authors measured plasma levels of acetaminophen and ibuprofen in 153 febrile children for 6 hours after a single dose of either acetaminophen (12.5 mg/kg) or ibuprofen (5 or 10 mg/kg). Cmax occurred about 2 1/2 hours before maximum antipyresis, when plasma acetaminophen or ibuprofen was 25 to 50% less than Cmax. Most plasma level data fit a one-compartment open model, and this suggests a pharmacodynamic basis for the observed lag between Cmax and maximum antipyretic response. Plasma levels (and AUCO----infinity) of ibuprofen 10 mg/kg were less than expected for a two-fold increase in dose. For acetaminophen, the tlag was less than ibuprofen, Ka was more than ibuprofen, and beta was less than ibuprofen. The ibuprofen beta was not dose dependent, but the Vd was dose and model dependent. In contrast, ibuprofen Clp was dose and model independent. Acetaminophen pharmacokinetics were similar to those previously reported. Initial temperature, race, gender, prior medications, or diagnosis did not confound the results for ibuprofen or acetaminophen. Accordingly, a pharmacodynamic basis is a more likely explanation for the initial temperature effects found previously for antipyretic drugs in children. Ibuprofen (5 and 10 mg/kg) AUCO-----infinity was higher in the older (greater than or equal to 2.5 yrs) children and the Vd and Clp were lower in the older children, when discriminated by age or pharmacokinetic parameters. The observed dose dependency of AUCO----infinity and the effect of age on ibuprofen disposition must be considered if pharmacokinetic interpretations are used to develop the antipyretic dose of ibuprofen in children.     

Multiple-dose pharmacokinetics of naproxen from a controlled-release tablet in healthy volunteers

The pharmacokinetics of a new controlled-release tablet of naproxen (750 mg) given once daily has been studied in healthy volunteers, in comparison with two doses of the conventional naproxen tablets (375 and 500 mg) administered twice daily. Steady-state plasma concentrations of naproxen were achieved after two days of repeated administration of both the controlled-release and the conventional tablets. On day seven, peak concentration, cowest concentration and the steady-state average plasma concentration values of the controlled-release tablet were significantly higher than those of 375 mg conventional tablet and comparable to those of 500 mg conventional tablet. Areas under the plasma concentration-time curve indicated an equal extent of absorption between the new and the conventional formulation. Overall the controlled-release tablet administered once daily mimicked a twice daily regimen so suggesting that the new formulation could be suitable for once daily dosing.     

Multiple-dose, linear, dose-proportional pharmacokinetics of retigabine in healthy volunteers

Retigabine, a first-in-class selective M-current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo-controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days. Fixed doses were given to the first four groups (200, 400, 500, and 600 mg per day). Titrated doses were given to group 5 in 100 mg increases every 4 days, achieving 700 mg per day on day 15. Serial blood samples were collected on days 1 and 15. Pharmacokinetic parameters were compared between days and among dose groups. After administration of a single dose, retigabine was rapidly absorbed, with maximum concentrations of 387 ng/ml (normalized to a 100 mg dose) occurring within 1.5 hours. Retigabine was eliminated with a mean terminal half-life of 8.0 hours and an apparent oral clearance of 0.70 L/h/kg in white subjects. In black subjects, retigabine clearance and volume of distribution were 25% and 30% lower, respectively, after normalizing by body weight, leading to higher exposure in this population. Retigabine's pharmocokinetics was linearly dose proportional. Steady-state pharmacokinetics was in agreement with single-dose pharmacokinetics, and the accumulation ratio was about 1.5. Retigabine and AWD21-360 trough evening concentrations were significantly lower (about 30% to 35%) than morning values. The titration regimen allowed for higher doses to be tolerated compared to the fixed-dose regimen. In conclusion, the pharmacokinetics of retigabine is linearly dose proportional for daily doses of 100 to 700 mg and is not modified on multiple administrations.     

Multiple-dose pharmacokinetics of diazepam following once-daily administration of a controlled-release capsule

The study was designed to determine the steady-state pharmacokinetic profile of diazepam and desmethyldiazepam following a 15-mg controlled-release capsule dosed once daily at either 7 a.m. or 11 p.m. compared with the respective profiles of the conventional 5-mg tablet dosed three times a day at 7 a.m., 12 p.m., and 5 p.m. Plasma concentrations of diazepam and desmethyldiazepam were assayed by an electron-capture gas-liquid chromatographic method. Plasma concentrations indicated that there were no differences between the pharmacokinetic profiles following the 7 a.m. or 11 p.m. dosings of the controlled-release capsule. Steady-state concentrations of diazepam were attained between days 7 and 9 during the controlled-release dosing, and the accumulation profiles are similar to those observed for the conventional tablet given three times a day. Nearly identical areas under the diazepam plasma concentration-time curves (AUC) on day 1 and at steady state for both regimens indicate equal extents of absorption from the two formulations. In addition, the steady-state AUCs for desmethyldiazepam were independent of formulation. The data indicate that a single daily dose of the 15-mg controlled-release capsule results in accumulation and steady-state profiles comparable to those observed following a regimen of the 5-mg conventional tablet three times a day.(ABSTRACT TRUNCATED AT 250 WORDS)     

Favipiravir inhibits acetaminophen sulfate formation but minimally affects systemic pharmacokinetics of acetaminophen

Aims

The antiviral agent favipiravir is likely to be co-prescribed with acetaminophen (paracetamol). The present study evaluated the possiblility of a pharmacokinetic interaction between favipiravir and acetaminophen, in vitro and in vivo.

Methods

The effect of favipivir on the transformation of acetaminophen to its glucuronide and sulfate metabolites was studied using a pooled human hepatic S9 fraction in vitro. The effect of acute and extended adminstration of favipiravir on the pharmacokinetics of acetaminophen and metabolites was evaluated in human volunteers.

Results

Favipiravir inhibited the in vitro formation of acetaminophen sulfate, but not acetaminophen glucuronide. In human volunteers, both acute (1 day) and extended (6 days) administration of favipiravir slightly but significantly increased (by about 20 %) systemic exposure to acetaminophen (total AUC), whereas C_max was not significantly changed. AUC for acetaminophen glucuronide was increased by 23 to 35 % above control by favipiravir, while AUC for acetaminophen sulfate was reduced by about 20 % compared to control. Urinary excretion of acetaminophen sulfate was likewise reduced to 44 to 65 % of control values during favipiravir co-administration, while excretion of acetaminophen glucuronide increased to 17 to 32 % above control.

Conclusion

Favipiravir inhibits acetaminophen sulfate formation in vitro and in vivo. However the increase in systemic exposure to acetaminophen due to favipiravir co-administration, though statistically significant, is small in magnitude and unlikely to be of clinical importance.     

Biopharmaceutical studies on drug/conjugated-metabolite interactions. II. Effect of acetaminophen sulfate on pharmacokinetics of acetaminophen in rats

The effect of conjugated-metabolite, acetaminophen sulfate (APAPS), on the pharmacokinetics of its parent drug, acetaimnophen (APAP), was examined in rats. Following the i.v. bolus administration of APAP with APAPS, the plasma elimination of APAP was delayed and the distribution volume of APAP was increased at the APAPS coadministration with 60 mg APAP equivalent per kg (eq/kg). The percentages of dose excreted in the urine and bile in 4 h as APAP and its conjugated metabolites, APAPS and acetaminophen glucuronide, were significantly decreased. On the other hand, following the i.v. bolus administration of APAP under the steady-state concentration of APAPS, the distribution volume and total body clearance of APAP were significantly increased. Competitive displacement in serum protein binding of APAP by APAPS was ascertained in vitro and in vivo. A part of the conflict between the bolus and infusion experiment may be explained by the changes in the distribution volume of APAP contributed to the APAPS concentration-dependent serum protein binding of APAP. It was speculated that the pharmacokinetics of APAP was partly interacted with APAPS by the displacement of serum protein binding.     

Multiple-dose pharmacokinetics of peginterferon alfa-2b in patients with renal insufficiency

What is already known about this subject?

• Current therapy for hepatitis C typically consists of pegylated interferon (PEG-IFN) alfa in combination with ribavirin.
• Pegylation of IFN alfa-2b confers a 10-fold increase in elimination half-life and a 30% reduction in volume of distribution compared with non-PEG-IFN alfa-2b.
• A single-dose pharmacokinetic study conducted in patients with chronic renal dysfunction has shown that renal elimination accounts for 30% of total PEG-IFN alfa-2b clearance and that PEG-IFN alfa-2b exposure increases with severity of renal insufficiency.

What this study adds

• Because the primary mechanism of IFN clearance is catabolism in the kidney, appropriate dosing of IFN-based therapies in patients with renal insufficiency is an important issue.
• This multiple-dose pharmacokinetic study shows that exposure to PEG-IFN alfa-2b is increased in patients with renal insufficiency, suggesting that doses of the drug should be reduced by 50% in patients with severe renal insufficiency and by 25% in those with moderate insufficiency.
• PEG-IFN alfa-2b was well tolerated in all patient groups during the 4-week treatment period, with similar adverse events occurring in patients with renal insufficiency and in those with normal renal function.

Aim

To evaluate the safety, tolerability and multiple-dose pharmacokinetics of pegylated interferon (PEG-IFN) alfa-2b in patients with moderate or severe renal insufficiency and in those with normal renal function.

Methods

In an open-label study, subjects with normal renal function (creatinine clearance >80 ml min⁻¹ per 1.73 m²) and patients with moderate (30–50 ml min⁻¹ per 1.73 m²) or severe (10–29 ml⁻¹ min⁻¹ per 1.73 m²) renal impairment received weekly injections of PEG-IFN alfa-2b (1.0 µg kg⁻¹) for 4 weeks. Safety assessments were made before each injection and blood samples were taken up to 168 h after the final dose.

Results

Renal insufficiency increased PEG-IFN alfa-2b exposure. Area under the curve for 0–τ (dosing interval of 168 h), AUC_τ, was increased 30% and 120% in patients with moderate or severe renal insufficiency, respectively. Mean maximum serum concentration was almost doubled in patients with severe insufficiency [1305.8 pg ml⁻¹; 95% confidence interval (CI) 825, 1786] compared with subjects with normal renal function (731.4 pg ml⁻¹; 95% CI 407, 1056), whereas the apparent volume of distribution was reduced (0.80 l kg⁻¹vs. 1.28 l kg⁻¹, respectively). Elimination half-life was extended in patients with moderate and severe renal insufficiency (65.6 h and 64.9 h, respectively) compared with subjects with normal renal function (51.5 h). Significant differences were observed in the AUC and C_max values of patients with severe renal dysfunction, compared with those who had normal renal function (P< 0.05; Kruskal–Wallis test). PEG-IFN alfa-2b was well tolerated and adverse events were similar in both treatment groups.

Conclusions

Exposure to PEG-IFN alfa-2b is increased in patients with renal insufficiency, suggesting that doses of the drug should be reduced by 50% in patients with severe renal insufficiency and by 25% in those with moderate insufficiency.     

Multiple-dose pharmacokinetics and safety of desloratadine in subjects with moderate hepatic impairment

Desloratadine, a nonsedating histamine H(1)-receptor antagonist, is metabolized to 3-hydroxy (3-OH) desloratadine. Impaired hepatic function could result in increased exposure to desloratadine. This study assessed possible differences in the pharmacokinetics and safety of desloratadine and 3-OH desloratadine in subjects (N = 21) with moderate hepatic dysfunction or normal liver function. Subjects were given desloratadine 5 mg once daily for 10 days and were assessed in several pharmacokinetic parameters. A similar degree of plasma protein binding to desloratadine and 3-OH desloratadine was observed in healthy volunteers and subjects with moderate hepatic impairment. All subjects with hepatic impairment were normal metabolizers. Three subjects with normal liver function, all African American, were identified as poor metabolizers. Exposure to desloratadine in the poor metabolizers was 2.6- to 6.5-fold greater than in other subjects with normal liver function. Eleven treatment-related adverse events, all mild to moderate in severity, were reported. Results suggest that subjects with moderate hepatic impairment experienced a greater increase in desloratadine exposure than subjects with normal liver function. Poor metabolizers had more exposure to desloratadine than normal metabolizers with or without hepatic impairment. Desloratadine administered at a daily dose of 5 mg was well tolerated.     

Effects of alcoholism on acetaminophen pharmacokinetics in man

As a nonspecific measure of increased metabolic clearance, the kinetics of acetaminophen was studied in a group of nondrinking controls and alcoholics who had ceased drinking within the previous 48 hours. After a single 1-Gm dose of acetaminophen, blood levels showed a significant increase in nondrinking controls over the alcoholics. The area under the curve for the alcoholics was smaller than that for the controls. Further studies are indicated to determine the quantities of the various metabolites of acetaminophen in both groups.     

Effect of cimetidine on acetaminophen pharmacokinetics in rats

The purpose of this investigation was to determine the effect of acute cimetidine administration on the elimination kinetics of acetaminophen in rats. Cimetidine, 80 mg/kg i.p., 30 min before i.v. injection of acetaminophen, 30 mg/kg, caused a small but statistically significant decrease in the total clearance and an increase in the biological half-life of acetaminophen in adult male rats. The partial metabolic clearance of acetaminophen to acetaminophen sulfate was decreased by cimetidine. The magnitude of the acute interaction of cimetidine with acetaminophen was not increased at a higher (150 mg/kg) dose of acetaminophen.     

多潘立酮对扑热息痛人体药物动力学的影响

本文应用高效液相色谱法测定了正常人口服扑热息痛和扑热息痛加多潘立酮时的扑热息痛血浓度,对2种情况下的药物动力学参数进行了统计学处理,结果表明,多潘立酮对扑热息痛的体内药物动力学没有影响,提示临床在合用多潘立酮时可按正常量给予扑热息痛。     

Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone plus pyrimethamine (Maloprim) in man.

1. The multiple-dose kinetics of dapsone (DDS), its major metabolite monoacetyldapsone (MADDS) and pyrimethamine (PYR) were studied in six healthy adult male volunteers following weekly administration of Maloprim (100 mg DDS plus 12.5 mg PYR). 2. After the last maintenance dose of Maloprim, the following kinetic parameters (mean values) were determined for DDS and PYR, respectively: maximum plasma concentration (Cmax) = 1,134 and 116 ng ml-1; elimination half-life (t1/2) = 23 and 105 h; plasma clearance (CL) = 37.6 and 15.9 ml h-1 kg-1 and apparent volume of distribution (Vss) = 1.20 and 2.29 l kg-1. The mean t1/2 of MADDS was 22 h. 3. The mean whole blood to plasma (B/P) and erythrocyte to plasma (E/P) concentration ratios for DDS were 1.04 and 1.09, respectively. MADDS had a B/P ratio of 0.69 and an E/P ratio of 0.33. The B/P and E/P ratios for PYR were 0.98 and 0.54, respectively. 4. The drug combination was assessed in vitro by measuring inhibition of re-invasion of two Plasmodium falciparum isolates grown in the presence of volunteers' sera. The chloroquine (CQ)- and PYR-sensitive FC-27 isolate was completely inhibited by the sera but the drug combination was ineffective against the CQ- and PYR-resistant K1 strain. The in vitro findings suggest that Maloprim may not be effective against strains of P. falciparum with a high level of resistance to pyrimethamine.     

Multiple-dose pharmacokinetics of the new H1-receptor antagonist tazifylline in healthy volunteers

The multiple-dose pharmacokinetics of the new H1-receptor antagonist, tazifylline, were investigated in healthy volunteers. From single-dose data, tazifylline appeared to be rapidly absorbed (median tmax of 0.6 h) and eliminated (t1/2 = 1.0 +/- 0.2 h). However, plasma levels measured on days 3 and 8 of the multiple-dose regimen (10 mg b.i.d. for 8 days) indicated moderate accumulation. A two-compartment model best described multiple-dose data with a terminal half-life of 15.6 +/- 7.6 h consistent with twice-daily dosing of tazifylline.