Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease

Objective:  The pharmacokinetic (PK) and pharmacodynamic (PD) responses to prasugrel were compared in three studies of healthy subjects vs. those with moderate or end-stage renal impairment.
Methods:  Two of the three protocols were parallel-design, open-label, single dose (60-mg prasugrel) studies in subjects with end-stage renal disease (ESRD; n  = 12) or moderate renal impairment ( n  = 10) and matched healthy subjects with normal renal function ( n  = 10). The third protocol was an open-label, single-dose escalation (5, 10, 30 and 60 mg prasugrel) study in subjects with ESRD ( n  = 16) and matched healthy subjects with normal renal function ( n  = 16). Plasma concentrations of prasugrel's active metabolite were determined and pharmacokinetic parameter estimates were derived. Maximum platelet aggregation (MPA) was measured by light transmission aggregometry using 20 μ m adenosine diphosphate as agonist.
Results:  Across all studies, prasugrel's C _max and AUC_{0– t} were 51% and 42% lower in subjects with ESRD than in healthy subjects. AUC_{0– t} did not differ between healthy subjects and subjects with moderate renal impairment. The magnitude of change and time-course profiles of MPA was similar for healthy subjects compared with subjects with moderate renal impairment and those with ESRD. Prasugrel was well-tolerated in all subjects.
Conclusion:  There was no difference in pharmacokinetics or PD responses between subjects with moderate renal impairment and healthy subjects. Despite significantly lower exposure to prasugrel's active metabolite in subjects with ESRD, MPA did not differ between healthy subjects and those with ESRD.     

Pharmacokinetics of losartan and its active carboxylic acid metabolite E-3174 in five ethnic populations of China

What is known and Objective: Interethnic variability in drug pharmacokinetics is well known. Our aim was to investigate whether the pharmacokinetics of losartan and its active carboxylic acid metabolite E‐3174 vary between subjects of five Chinese ethnicities (Han, Mongolian, Korean, Hui and Uigur). Methods: Fifty healthy subjects (five men and five women of each ethnicity) were recruited, and each received 50‐mg dose of losartan in tablet form. Fourteen blood samples were collected for each subject over a 24‐h period after drug administration. The concentrations of losartan and its active carboxylic acid metabolite E‐3174 in plasma were determined by high‐performance liquid chromatography/fluorescence (HPLC/FLU) method, and the pharmacokinetic parameters were calculated by DAS 2.0 software and compared by SPSS 16.0 software. Pharmacokinetic parameters, including area under the curve from 0 h to the last measured point 24 h [AUC_(0–24)], area under the curve from 0 h to infinite time [AUC_(0–∞)], peak plasma concentration (C_max), time to reach C_max (t_max), oral clearance (CL), oral volume of distribution (V_d) and elimination half‐life (t_1/2), were determined following a single oral dose of losartan. Results and Discussion: The t_1/2 values of losartan and its active carboxylic acid metabolite E‐3174 showed significant differences across the five ethnicities. After normalization by weight, no ethnicity‐based difference was noted in the pharmacokinetic parameters of losartan. However, there were significant differences in C_max and V_d of the active carboxylic acid metabolite E‐3174 for Han and Mongolian subjects, compared with the other three ethnic groups. There was a high linear correlation between weight and C_max, AUC_(0–24), AUC_(0–∞), CL and V_d. What is new and Conclusion: Ethnicity was associated with significant differences in the single‐dose pharmacokinetics of losartan’s active carboxylic acid metabolite E‐3174 in healthy subjects of the five main ethnic groups in China.     

Platelet function normalization after a prasugrel loading‐dose: time‐dependent effect of platelet supplementation

Summary. Background: Hemostatic benefits of platelet transfusions in thienopyridine‐treated acute coronary syndrome (ACS) patients may be compromised by residual metabolite in circulation.Objectives: To estimate the earliest time after a prasugrel loading‐dose when added platelets are no longer inhibited by prasugrel's active metabolite.Methods: Baseline platelet reactivity of healthy subjects (n = 25, 30 ± 5 years, 68% male) on ASA 325 mg was tested using maximum platelet aggregation (MPA, ADP 20 μm ) and VerifyNow^® P2Y12 and was followed by a 60 mg prasugrel loading‐dose. At 2, 6, 12 and 24 h post‐dose, fresh concentrated platelets from untreated donors were added ex‐vivo to subjects’ blood, raising platelet counts by 0% (control), 40%, 60% and 80%. To estimate the earliest time when prasugrel's active metabolite's inhibitory effect on the added platelets ceases, platelet function in supplemented samples was compared across time‐points to identify the time when effect of supplementation on platelet function stabilized (i.e. the increase in platelet reactivity was statistically similar to that at the next time‐point).Results: Supplemented samples showed concentration‐dependent increases in platelet reactivity vs. respective controls by both MPA and VerifyNow^® at all assessment time‐points. For each supplementation level, platelet reactivity showed a sharp increase from 2 to 6 h but was stable (P = NS) between 6 and 12 h.Conclusions: The earliest measured time when supplemented platelets were not inhibited by circulating active metabolite of prasugrel was 6 h after a prasugrel loading‐dose. These findings may have important implications for prasugrel‐treated ACS patients requiring platelet transfusions during surgery.     

Open-label,Single-dose Studies of the Pharmacokinetics of Edaravone in Subjects with Mild,Moderate, or Severe Hepatic Impairment Compared to Subjects with Normal Hepatic Functioning

PurposeTwo studies were conducted to assess the pharmacokinetic (PK) properties and tolerability of edaravone in Japanese subjects with mild to moderate hepatic impairment or normal hepatic functioning (study 1), and in white subjects with severe hepatic impairment compared to subjects with normal hepatic functioning (study 2).MethodsStudies 1 and 2 were multicenter, open-label, single-dose studies that included subjects aged 18–75 years. In study 1, subjects were stratified into 3 different groups of hepatic functioning according to Child-Pugh score: mild hepatic impairment, score 5 or 6 (n = 8); moderate hepatic impairment, score 7–9 (n = 6); or normal hepatic functioning (n = 8). In study 2, subjects had severe hepatic impairment (Child-Pugh score 10–14; n = 6) or normal hepatic functioning (n = 6). In both studies, all subjects were given edaravone 30 mg IV infused over 60 min on the morning of day 1. Blood samples for use in PK analyses were collected from days 1–3. The PK properties (C_max, AUC_0–last, and AUC_0–∞) of edaravone and its sulfate conjugate metabolite were measured.FindingsIn study 1, the geometric least-squares mean (GLSM) C_max and AUC_0–∞ of unchanged edaravone were 1.203- and 1.065-fold greater, respectively, in subjects with mild hepatic impairment versus normal hepatic functioning, and were 1.235- and 1.142-fold greater, respectively, in subjects with moderate hepatic impairment versus normal hepatic functioning. In study 2, GLSM C_max and AUC_0–∞ of unchanged edaravone were 1.203- and 1.190-fold greater, respectively, in subjects with severe hepatic impairment versus normal hepatic functioning. In both studies the AUC_0–last, AUC_0–∞, unbound AUC from time zero to infinity, and C_max of unchanged edaravone were increased slightly with increases in Child-Pugh classification. No adverse events considered related to edaravone were reported, except for 1 case of sinus bradycardia in a subject with normal hepatic functioning in study 2. The event was moderate in severity, considered as possibly related to edaravone, and resolved during the study.ImplicationsMild to moderate and severe hepatic impairment had no apparent clinically significant effects on the PK profile of edaravone in Japanese and white subjects, respectively, relative to individuals with normal hepatic functioning, and there were no notable tolerability concerns. Thus, edaravone dosage adjustments are unlikely to be needed in edaravone-treated patients with mild to moderate and severe hepatic impairment. ClinicalTrials.gov identifiers: NCT03289234 (mild to moderate hepatic impairment) and NCT03664544 (severe hepatic impairment).     

Influence of Renal and Hepatic Impairment on the Pharmacokinetic and Pharmacodynamic Properties and Tolerability of Fluticasone Furoate and Vilanterol in Combination

BackgroundRenal and hepatic disease may lead to alterations in drug absorption, distribution, and elimination, and, therefore, the potential effect of renal and hepatic impairment should be investigated in drugs under development.ObjectiveTo assess the effects of renal and hepatic impairment on the pharmacokinetic and pharmacodynamic properties and tolerability of fluticasone furoate/vilanterol (FF/VI) administered in combination.MethodsTwo open-label, parallel-group studies were conducted. Eligible study participants included adults with severe renal impairment (CrCl <30 mL/min) and those with mild, moderate, or severe hepatic impairment (by Child-Pugh classification). Patients were matched with healthy subjects. Participants received 7 days of inhaled FF/VI 200/25 or 100/12.5 μg (severe hepatic impairment only) once daily in the morning. Lack of effect was defined as an upper 90% confidence limit of the C_max and AUC geometric mean impaired:healthy ratios (GMRs) of <2.ResultsStudy participants included patients with severe renal impairment (n = 9) or with mild (n = 9), moderate (n = 9), or severe (n = 8) hepatic impairment, together with matched healthy subjects (n = 9 per study). Lack of effect of severe renal impairment was demonstrated with FF (GMRs [90% CI]: C_max, 0.96 [0.57–1.61]; AUC_0–24, 0.91 [0.60–1.38]) and VI (C_max, 0.70 [0.49–1.00]; AUC_0–24, 1.56 [1.27–1.92]). Day-7 dose-normalized FF AUC_0–24 was greater in the groups with mild, moderate, and severe hepatic impairment than in healthy subjects (GMRs [90% CI]: 1.34 [0.82–2.20], 1.83 [1.11–2.99], and 1.75 [1.05–2.91], respectively); lack of effect was not demonstrated. There was no effect of hepatic impairment on dose-normalized VI C_max or AUC_0–24. Apart from reduced serum cortisol weighted mean (0–24 hour) in patients with moderate hepatic impairment (34% reduction [90% CI, 11%–51%] compared with healthy subjects), there was no evidence of a difference in heart rate, serum potassium, or 24-hour serum cortisol between patients with severe renal impairment of any hepatic impairment and healthy subjects. No safety concerns were identified in any of the groups with impairment or their matched healthy controls.ConclusionsSevere renal impairment had no apparent clinically relevant effects on the pharmacokinetic or pharmacodynamic properties or tolerability of FF/VI. Hepatic impairment had no apparent effect on VI systemic exposure but increased FF exposure. Fluticasone furoate was associated with reduced serum cortisol in patients with moderate hepatic impairment. These data suggest that caution should be exercised when prescribing FF/VI in patients with moderate or severe hepatic impairment due to a risk for unwanted systemic corticosteroid effects associated with increased FF systemic exposure. Clinicaltrials.gov identifiers: NCT01266941 and NCT01266980.     

Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently

Prasugrel and clopidogrel inhibit platelet aggregation through active metabolite formation. Prasugrel's active metabolite (R-138727) is formed primarily by cytochrome P450 (CYP) 3A and CYP2B6, with roles for CYP2C9 and CYP2C19. Clopidogrel's activation involves two sequential steps by CYP3A, CYP1A2, CYP2C9, CYP2C19, and/or CYP2B6. In a randomized crossover study, healthy subjects received a loading dose (LD) of prasugrel (60 mg) or clopidogrel (300 mg), followed by five daily maintenance doses (MDs) (15 and 75 mg, respectively) with or without the potent CYP3A inhibitor ketoconazole (400 mg/day). Subjects had a 2-week washout between periods. Ketoconazole decreased R-138727 and clopidogrel active metabolite Cmax (maximum plasma concentration) 34-61% after prasugrel and clopidogrel dosing. Ketoconazole did not affect R-138727 exposure or prasugrel's inhibition of platelet aggregation (IPA). Ketoconazole decreased clopidogrel's active metabolite AUC0-24 (area under the concentration-time curve to 24 h postdose) 22% (LD) to 29% (MD) and reduced IPA 28% (LD) to 33% (MD). We conclude that CYP3A4 and CYP3A5 inhibition by ketoconazole affects formation of clopidogrel's but not prasugrel's active metabolite. The decreased formation of clopidogrel's active metabolite is associated with reduced IPA.     

Aspirin has little additional anti‐platelet effect in healthy volunteers receiving prasugrel

Summary. Background: Strong P2Y₁₂ blockade, as can be achieved with novel anti‐platelet agents such as prasugrel, has been shown in vitro to inhibit both ADP and thromboxane A₂‐mediated pathways of platelet aggregation, calling into question the need for the concomitant use of aspirin. Objective: The present study investigated the hypothesis that aspirin provides little additional anti‐aggregatory effect in a group of healthy volunteers taking prasugrel. Study participants/methods: In all, 9 males, aged 18 to 40 years, enrolled into the 21‐day study. Prasugrel was loaded at 60 mg on day 1 and maintained at 10 mg until day 21. At day 8, aspirin 75 mg was introduced and the dose increased to 300 mg on day 15. On days 0, 7, 14 and 21, platelet function was assessed by aggregometry, response to treatments was determined by VerifyNow? and urine samples were collected for quantification of prostanoid metabolites. Results: At day 7, aggregation responses to a range of platelet agonists were reduced and there was only a small further inhibition of aggregation to TRAP‐6, collagen and epinephrine at days 14 and 21, when aspirin was included with prasugrel. Urinary prostanoid metabolites were unaffected by prasugrel, and were reduced by the addition of aspirin, independent of dose. Conclusions: In healthy volunteers, prasugrel produces a strong anti‐aggregatory effect, which is little enhanced by the addition of aspirin. The addition of aspirin as a dual‐therapy with potent P2Y₁₂ receptor inhibitors warrants further investigation.     

Influence of hepatic impairment on the pharmacokinetics and pharmacodynamics of the P2Y12 receptor antagonist selatogrel

Selatogrel is a potent and selective reversible P2Y12 receptor antagonist in development for early treatment of acute myocardial infarction via subcutaneous (s.c.) self‐injection. Selatogrel is almost exclusively eliminated via the hepatobiliary route. Hepatic impairment is associated with reduced drug clearance and primary hemostasis. This single‐center, open‐label study investigated the effect of mild and moderate hepatic impairment on pharmacokinetics (PK) and pharmacodynamics (PD) of a single s.c. dose of selatogrel (16 mg). The study included groups of eight subjects with mild and moderate hepatic impairment, and matched healthy control subjects. Compared to healthy subjects, exposure to selatogrel in subjects with mild and moderate hepatic impairment was 30% and 108% (maximum plasma concentration [C _max]) and 47% and 212% (area under the concentration‐time curve from zero to infinity [AUC_0–∞]) higher, respectively. Hepatic impairment was associated with lower clearance and volume of distribution, whereas plasma protein binding was not affected. Marked inhibition of platelet aggregation (IPA > 80%) was attained within 30 min in all subjects and hepatic impairment prolonged IPA duration. Area under the effect curve was 60% and 160% higher in subjects with mild and moderate hepatic impairment, respectively. PK/PD modeling identified a change in the relationship between exposure and IPA, with a steeper concentration‐effect relationship in healthy subjects compared to subjects with hepatic impairment. The combination of higher exposure and lower half‐maximum inhibitory concentration resulted in longer lasting effect. In conclusion, hepatic impairment alters the PK/PD relationship leading to prolonged effects. Therefore, dose adjustments may be warranted in subjects with moderate hepatic impairment.

Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Selatogrel is a potent and selective P2Y12 receptor antagonist for subcutaneous self‐administration by patients when they suspect onset of an acute myocardial infarction.WHAT QUESTION DID THIS STUDY ADDRESS?This study investigated the influence of mild and moderate hepatic impairment on the pharmacokinetics (PK) and pharmacodynamics (PD) of selatogrel.WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?Increased hepatic impairment was associated with higher exposure to selatogrel due to lower clearance and volume of distribution. The concentration‐effect (inhibition of platelet aggregation) relationship changed in hepatic impairment leading to higher drug sensitivity.HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?Hepatic impairment does not only change the PK of P2Y12 receptor antagonists but, due to its effect on primary hemostasis, also their PD.     

St John's wort greatly decreases the plasma concentrations of oral S-ketamine

Ketamine is an intravenous anaesthetic and analgesic agent but it can also be used orally as an adjuvant in the treatment of chronic pain. This study investigated the effect of the herbal antidepressant St John’s wort, an inducer of cytochrome P450 3A4 (CYP3A4), on the pharmacokinetics and pharmacodynamics of oral S‐ketamine. In a randomized cross‐over study with two phases, 12 healthy subjects were pretreated with oral St John’s wort or placebo for 14 days. On day 14, they were given an oral dose of 0.3 mg/kg of S‐ketamine. Plasma concentrations of ketamine and norketamine were measured for 24 h and pharmacodynamic variables for 12 h. St John’s wort decreased the mean area under the plasma concentration–time curve (AUC_0–∞) of ketamine by 58% (P < 0.001) and decreased the peak plasma concentration (C_max) of ketamine by 66% (P < 0.001) when compared with placebo. Mean C_max of norketamine (the major metabolite of ketamine) was decreased by 23% (P = 0.002) and mean AUC_0–∞ of norketamine by 18% (P < 0.001) by St John’s wort. There was a statistically significant linear correlation between the self‐reported drug effect and C_max of ketamine (r = 0.55; P < 0.01). St John’s wort greatly decreased the exposure to oral S‐ketamine in healthy volunteers. Although this decrease was not associated with significant changes in the analgesic or behavioural effects of ketamine in the present study, usual doses of S‐ketamine may become ineffective if used concomitantly with St John’s wort.     

Pharmacokinetics of Single-dose Ertugliflozin in Patients With Hepatic Impairment

Purpose

Ertugliflozin, an oral, highly selective inhibitor of the sodium-glucose cotransporter 2, is approved in the United States and the European Union for the treatment of adults with type 2 diabetes mellitus. Hepatic impairment may affect, to varying degrees, the absorption, metabolism, and excretion of drugs and may be associated with a lower plasma protein binding compared with that in healthy individuals. This study was conducted to assess the effect of hepatic impairment on the pharmacokinetic (PK), safety, and tolerability profiles of ertugliflozin after administration of a single, 15-mg oral dose.

Pharmacokinetic Effects of Diphenhydramine or Oxycodone in Simulated Acetaminophen Overdose

Objectives: To determine the effects of co‐ingested diphenhydramine (DPH) or oxycodone (OXY) on the absorption kinetics of simulated acetaminophen (APAP) overdose. Methods: This was an institutional review board–approved, prospective crossover study of ten healthy human volunteers ingesting 5 grams of APAP, 5 grams of APAP + 250 mg of DPH (APAP+DPH), or 5 grams of APAP + 0.5 mg/kg of OXY (APAP+OXY). Serum APAP concentrations (APAPs) were measured hourly from zero through eight hours and again at 24 hours, and basic noncompartmental pharmacokinetic parameters were compared. Results: For APAP alone, the mean parameters were: maximum APAP concentration ([APAP]_max) 71.8 μg/mL, time to peak [APAP] (t_max) 1.71 hours, and area under the receiver operating characteristic curve (AUC_0–8) 318.3 μg‐hr/mL. For APAP+DPH, the mean parameters were: [APAP]_max 67.6 μg/mL, t_max 1.90 hours, and AUC_0–8 297.7 μg‐hr/mL. For APAP+OXY, the parameters were: [APAP]_max 42.9 μg/mL, t_max 2.87 hours, and AUC_0–8 232.1 μg‐hr/mL. Compared with APAP alone, APAP+OXY had a 27% lower AUC, a 40% lower [APAP]_max, and a 68% longer t_max. Co‐ingested DPH had no significant effect on APAP absorption, except a 6% decrease in the AUC. Conclusions: Co‐ingested OXY, but not DPH, delayed absorption of APAP. This suggests a potential role for activated charcoal administration beyond one hour postingestion after mixed ingestions that include OXY.     

Effect of fluconazole on the pharmacokinetics of halofantrine in healthy volunteers

Background: Halofantrine, an antimalarial drug used in endemic areas such as the tropics is mainly metabolized by CYP3A4 to the active metabolite N‐desbutylhalofantrine. Fluconazole, an antifungal agent and an inhibitor of CYP3A4 is an established part of the therapy in HIV patients, who in turn are prone to malaria in the tropics. This study investigated the effect of fluconazole on the pharmacokinetics of halofantrine after concurrent administration of the two drugs. Methods: The effect of fluconazole on the pharmacokinetics of the antimalarial drug halofantrine was evaluated in 15 healthy volunteers in a Latin Square crossover design. The subjects received a single oral dose of 500 mg halofantrine hydrochloride alone or with 50 mg fluconazole after an overnight fast. Venous blood samples were collected during the next 336 h and analysed by HPLC for halofantrine and its active metabolite N‐desbutylhalofantrine. Results: Co‐administration of fluconazole did not alter the pharmacokinetics of halofantrine significantly with the exception of elimination t_1/2 that was significantly increased by 25% (P < 0·05). In contrast, fluconazole significantly altered the pharmacokinetic parameters of the active metabolite by reducing C_max, AUC and metabolite ratio (N‐desbutylhalofantrine/halofantrine) between 35 and 41% (P < 0·05) while increasing t_max by 50%. The 90% confidence intervals of the ratio of the geometric means (with/without fluconazole) were contained within 80–125% for halofantrine but outside this range for N‐desbutylhalofantrine. Conclusion: The decreased plasma concentrations of the metabolite are presumably caused by metabolic inhibition of CYP3A4 by fluconazole. Although the therapeutic consequences of this interaction are not clear caution should be exercised when co‐administering both drugs to avoid accumulation and subsequent cardiotoxic effects of halofantrine.     

Pharmacokinetic basis of the antiplatelet action of prasugrel

Prasugrel is the most recent development of thienopyridine-type antiplatelet drugs. Like the earlier-generation thienopyridines, i.e. ticlopidine and clopidogrel, prasugrel is also an inactive prodrug that requires metabolic processing in vivo to generate the active antiplatelet metabolite. The efficacy of this bioactivation is the key determinant for the pharmacodynamic potency of the compound, i.e. the irreversible blockade of the platelet P2Y12-ADP receptor. Prasugrel is rapidly absorbed from the gut. After oral administration of standard-loading doses of 60 mg, maximum plasma levels of the active metabolite are achieved within 1 h, effective, maximum inhibition of platelet aggregation at 1-2 h. Bioconversion of prasugrel into the active metabolite requires two metabolic steps that occur in sequence. The first is the generation of a thiolactone-intermediate, mainly by carboxyesterases-2 in the intestine, the second the cytochrome (CYP)-dependent conversion of the thiolactone into the active metabolite. This second step involves several cytochromes, most notably CYP3A4, CYP2C19, CYP2B6, and CYP2C9. The enzymatic generation of the active metabolite of prasugrel is much more effective than that of clopidogrel where only about 5% of oral clopidogrel is transformed into the active compound by two-step CYP-dependent procedures. About 70% of prasugrel metabolites are excreted in the urine and 30% in the feces. The molar potency of the respective active metabolites of prasugrel and clopidogrel is identical. Thus, the more rapid onset, higher potency and lower interindividual variability of antiplatelet effects of prasugrel as compared to clopidogrel in vivo are entirely because of its more efficient pharmacokinetics.     

Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel

Background and objectives: Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter‐individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel. Methods: Seventy‐six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non‐compartmental analysis was used to determine peak plasma concentration (C_max), time to peak plasma concentration (T_max), elimination half‐life (t_1/2e), and area under the curve (AUC_0→∞). Results: One‐third of volunteers were smokers (n = 27) and one‐half had abnormal body weight (n = 39). Smokers had lower AUC_0→∞ (smokers: 6·24 ± 2·32 μg/h/mL vs. non‐smokers: 8·93 ± 3·80 μg/h/mL, P < 0·001) and shorter half‐life (smokers: 5·46 ± 2·99 vs. non‐smokers: 8·43 ± 4·26, P = 0·001). Smoking behaviour had no influence on C_max (P = 0·3) and T_max (P = 0·7). There was no statistically significant difference in C_max, AUC_0→∞, T_max and t_1/2e between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean ± SE; 26·93 ± 0·16 vs. 23·11 ± 0·27). In general, the pharmacokinetic parameters were characterized by considerable inter‐individual differences (C_max = 3·09 ± 0·99 μg/mL, CV = 32%), (T_max =0·76 ± 0·24 h, CV = 31·6%), (AUC_0→∞ = 7·98 ± 3·58 μg/h/mL, CV = 44·8%), and (t_1/2e = 7·38 ± 4·10 h, CV = 55·6%). Conclusion: Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking‐cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed.     

Effect of soybean administration on the pharmacokinetics of carbamazepine and omeprazole in rats

Influence of soybean administration on the bioavailability of carbamazepine and omeprazole was studied after single dose administration of soybean (10 g/kg p.o.) or after chronic administration of soybean (50% w/w mixed with normal feed) for 15 days in rats. Carbamazepine was administered orally at a dose of 10 mg/kg and omeprazole at a dose of 20 mg/kg. Soybean decreased the bioavailability of carbamazepine after both single dose and chronic administration. It produced a significant decrease in C_max, T_max, AUC_0–t of carbamazepine after single dose administration and increased the plasma clearance and V_d along with decrease in C_max, T_max, AUC_0–t and AUC_{0– ∞} after chronic administration. On the contrary, soybean administration increased the bioavailability of omeprazole by producing an increase in C_max, AUC_0–t and AUC_{0– ∞} and a decrease in V_d after single dose administration and a decrease in plasma clearance along with increase in C_max, AUC_0–t and AUC_{0– ∞} after chronic administration. The half‐life of omeprazole was also increased after both acute and chronic administration of soybean. It was concluded that soybean decreases the bioavailability of carbamazepine and increases the bioavailability of omeprazole after both single dose and chronic administration.     

Pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers

What is known and Objective: Ivabradine is a novel heart rate‐lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Our objective was to evaluate a possible pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers. Methods: The study consisted of two periods: Period 1 (Reference), when each volunteer received a single dose of 10 mg ivabradine and Period 2 (Test), when each volunteer received a single dose of 10 mg ivabradine and 400 mg carbamazepine. Between the two periods, the subjects were treated for 15 days with a single daily dose of 400 mg carbamazepine. Plasma concentrations of ivabradine were determined during a 12‐h period following drug administration, using a high‐throughput liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment period were calculated using non‐compartmental and compartmental analysis to determine if there were statistically significant differences. Results and Discussion: In the two periods of treatments, the mean peak plasma concentrations (C_max) were 16·25 ng/mL (ivabradine alone) and 3·69 ng/mL (ivabradine after pretreatment with carbamazepine). The time taken to reach C_max, t_max, were 0·97 and 1·14 h, respectively, and the total areas under the curve (AUC_0‐∞) were 52·49 and 10·33 ng h/mL, respectively. These differences were statistically significant for C_max and AUC_0‐∞ when ivabradine was administered with carbamazepine, whereas they were not for t_max, half‐life and mean residence time. What is new and Conclusion: TCarbamazepine interacts with ivabradine in healthy volunteers, and lowers its bioavailability by about 80%. This magnitude of effect is likley to be clinically significant.     

Comparison of Pharmacokinetics of Two Fenofibrate Tablet Formulations in Healthy Human Subjects

Background

Fenofibrate is a serum lipid-lowering agent used as an adjunct to diet in patients with hypercholesterolemia and hypertriglyceridemia. The new fenofibrate tablet formulation was developed as a pharmaceutical equivalent to the marketed tablet formulation containing 145 mg.

Objective

The objective of this study was to compare the pharmacokinetics and safety of 2 tablet formulations containing 145 mg of fenofibrate (CAS number 49562-28-9) in healthy human subjects.

Methods

The study was a randomized, 2-treatment, 3-period, 3-sequence, single-dose, 3-way crossover, partial replicate bioequivalence study in healthy human subjects under fasting conditions. Eligible subjects received each treatment in a crossover manner according to the randomization schedule. Replicate dosing was conducted for the reference formulation to determine its intrasubject variability. The predose blood sample was taken within 1 hour before dosing, and serial blood sampling was performed up to 72.0 hours’ postdose. The analysis of plasma samples for concentrations of fenofibric acid, the active metabolite of fenofibrate, was conducted by using a validated LC-MS/MS method. Bioequivalence was to be concluded if the 90% CIs as constructed were within the range of 80% to 125% for C_max, AUC_0–t, and AUC_0–∞ for fenofibric acid. Subjects were monitored for safety and tolerability throughout the study.

Results

15 healthy human subjects between 18 and 45 years of age and having body mass index between 18.5 and 30 kg/m² were recruited into the study. The 90% CIs for the test/reference mean ratios of the ln-transformed pharmacokinetic variables C_max, AUC_0–t, and AUC_0–∞ were within the conventional bioequivalence range of 80% to 125%. Both formulations were well tolerated after a single oral dose in these healthy male subjects.

Conclusions

Both fenofibrate tablet formulations demonstrated equivalent rates and extent of systemic absorption, and hence were considered bioequivalent.     

The pharmacokinetics of fluconazole in healthy Chinese adult volunteers: influence of ethnicity and gender

Objective: The purpose of the present study was to investigate and compare the influence of ethnicity (including Han, Mongolian, Korean, Hui and Uygur) and gender on the pharmacokinetics of fluconazole in healthy adult volunteers after administration of 200‐mg fluconazole tablet. Methods: Ten healthy subjects (five males and five females) of each ethnicity were recruited and given a single 200‐mg dose of fluconazole in tablet form. Blood samples were obtained before dosing and at various predetermined time points after administration up to 96 h. Drug levels were measured by high‐performance liquid chromatography. The blood concentration–time profiles were analyzed using a non‐compartmental approach to estimate the absorption parameters (AUC_(0–96), C_max and t_max), the distribution parameter (V_d) and the disposition parameters (t_1/2 and CL). Results: Ethnicity did not affect the parameter estimates, but gender did. However, the gender differences in pharmacokinetic parameter could be accounted for by differences in weight. There was a high linear correlation between weight and ln C_max, ln AUC (ln means natural logarithmic transformation), V_d and CL. Conclusions: Ethnicity (Chinese Han, Mongolian, Korean, Hui and Uygur) influences the pharmacokinetics of fluconazole tablet. However, there were statistically significant gender differences in AUC, C_max, V_d and CL. But these could be accounted for by weight differences. If fluconazole dose‐adjustment is deemed necessary, this can be done on a weight basis rather than gender basis.     

Pharmacokinetics,safety, and tolerability of sulcardine sulfate: an open‐label,single‐dose,randomized study in healthy Chinese subjects

Sulcardine sulfate (Sul) is a novel anti‐arrhythmic agent as a potential treatment for atrial fibrillation and ventricular arrhythmias. This study was conducted to investigate the pharmacokinetic profile, safety, and tolerability of Sul in healthy Chinese subjects. In this open‐label, single‐dose, randomized study, 10 healthy subjects were assigned to receive Sul doses of 200, 400, and 800 mg under fasting conditions (Cohorts A, B, and C, respectively) or 400 mg under fed conditions (Cohort D). The study incorporated a crossover design, separated by a seven‐day washout period. Blood samples were collected before treatment and at successive time intervals up to 48 h after treatment. Sul concentrations in plasma samples were determined using a validated LC‐MS/MS method. Tolerability was determined by clinical evaluation and adverse event (AE) monitoring. Pharmacokinetic results demonstrated that C_max and AUC_(0–t) of Sul increased with an increasing dose. The mean t_1/2 values for Cohorts A, B, and C were 16.85, 17.66, and 11.87 h, respectively. No statistically significant differences were observed between men and women for the main pharmacokinetic parameters, with the exception of t_1/2 in Cohorts B and C. No significant differences were observed in the absorption and bioavailability of Sul between the fed and fasted states (P > 0.05). Four subjects reported mild AEs during the study. No serious AEs were reported. Sul was shown to be safe and well tolerated in healthy Chinese subjects. Pharmacokinetics studies demonstrated that Sul has adequate oral absorption and bioavailability properties.     

No pharmacokinetic interactions between mycophenolic acid and tacrolimus in renal transplant recipients

Objective:  The aim of this study was to investigate drug interactions between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF) and tacrolimus, as well as the impact of CYP3A5 and UGT2B7 genetic polymorphisms on these drug interactions in 71 Japanese renal transplant recipients. Methods:  Recipients received combination immunosuppressive therapy consisting of tacrolimus and MMF. On day 28 after transplantation, the concentrations of MPA and tacrolimus were measured by high‐performance liquid chromatography and microparticle enzyme immunoassay respectively. Results:  Acute rejection was over twice more common in recipients with a total area under the observed plasma concentration‐time curve (AUC_0–12) of MPA <70 μg·h/mL than in those with higher values AUC_0–12 values (17% vs. 7%).Using this cut‐off AUC value, sensitivity was 70·6% and specificity 55·6% for acute rejection (AR). There was no change in AUC_0–12, maximum plasma concentration, trough plasma concentration, or oral clearance of tacrolimus with variation in dosage or AUC of MPA. There were also no significant differences in the MPA pharmacokinetic parameters among three tacrolimus C₀ groups: 5 ≤ C₀ < 10, 10 ≤ C₀ < 15 and 15 ≤C₀ < 20 ng/mL. Furthermore, there were no significant differences in MPA pharmacokinetic parameters between the UGT2B7*1/*1 and *1/*2 genotype groups having the CYP3A5*1 allele or the CYP3A5*3/*3 genotype. Conclusion:  Therapeutic dosages of MMF, do not significantly influence tacrolimus pharmacokinetics, and vice versa. Consequently, MPA and tacrolimus can be safely combined; however, it is necessary to monitor the plasma concentrations of each immunosuppressive agent to minimize acute rejection.