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The objective of this study was to evaluate whether cytochrome P450 (CYP)4F2 is involved in the exposure of vitamin K1 through a drug interaction study with ketoconazole, a CYP4F2 inhibitor, and a pharmacogenetic study with CYP4F2*3. Twenty‐one participants with different CYP4F2*3 polymorphisms were enrolled (8 for *1/*1, 7 for *1/*3, and 6 for *3/*3). All participants were treated twice daily for 5 days with 200 mg of ketoconazole or placebo. Finally, a single dose of 10 mg vitamin K1 was administered, plasma levels of vitamin K1 were measured, and its pharmacokinetics was assessed. Ketoconazole elevated the plasma levels of vitamin K1 and increased the average area under the concentration‐time curve (AUCinf) and peak concentration by 41% and 40%, respectively. CYP4F2*3 polymorphism also affected plasma levels of vitamin K1 and its pharmacokinetics in a gene dose–dependent manner. The average AUCinf value was 659.8 ng·h/mL for CYP4F2*1/*1, 878.1 ng·h/mL for CYP4F2*1/*3, and 1125.2 ng·h/mL for CYP4F2*3/*3 (P =.010). This study revealed that ketoconazole and CYP4F2*3 polymorphism substantially increased the exposure of vitamin K1 in humans. These findings provide a plausible explanation for variations in warfarin dose requirements resulting from interindividual variations in vitamin K1 exposure due to CYP4F2‐related drug interactions and genetic polymorphisms. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate whether cytochrome P450 (CYP)4F2 is involved in the exposure of vitamin K1 through a drug interaction study with ketoconazole, a CYP4F2 inhibitor, and a pharmacogenetic study with CYP4F2*3. Twenty‐one participants with different CYP4F2*3 polymorphisms were enrolled (8 for *1/*1, 7 for *1/*3, and 6 for *3/*3). All participants were treated twice daily for 5 days with 200 mg of ketoconazole or placebo. Finally, a single dose of 10 mg vitamin K1 was administered, plasma levels of vitamin K1 were measured, and its pharmacokinetics was assessed. Ketoconazole elevated the plasma levels of vitamin K1 and increased the average area under the concentration‐time curve (AUCinf) and peak concentration by 41% and 40%, respectively. CYP4F2*3 polymorphism also affected plasma levels of vitamin K1 and its pharmacokinetics in a gene dose–dependent manner. The average AUCinf value was 659.8 ng·h/mL for CYP4F2*1/*1, 878.1 ng·h/mL for CYP4F2*1/*3, and 1125.2 ng·h/mL for CYP4F2*3/*3 (P =.010). This study revealed that ketoconazole and CYP4F2*3 polymorphism substantially increased the exposure of vitamin K1 in humans. These findings provide a plausible explanation for variations in warfarin dose requirements resulting from interindividual variations in vitamin K1 exposure due to CYP4F2‐related drug interactions and genetic polymorphisms. [ABSTRACT FROM AUTHOR]

The combination of calcium channel blockers (CCB) and angiotensin receptor blockers (ARB) for the treatment of hypertension showed improved efficacy and safety. Amlodipine is mainly metabolized by cytochrome P450 (CYP) 3A4, whereas losartan is metabolized by CYP2C9 and CYP3A4. The potential pharmacokinetic interactions between amlodipine and losartan were assessed. An open‐label, three‐period, fixed‐sequence trial was conducted. Amlodipine, losartan and combined amlodipine and losartan were administered to 24 healthy male participants during periods 1, 2 and 3, respectively, for 9 days each. The pharmacokinetics of amlodipine, losartan and EXP‐3174, an active metabolite of losartan, were assessed at steady‐state. Twenty participants completed the study without serious adverse events. Losartan did not influence the exposure of amlodipine at steady‐state (AUCτ, 165.15 ng h/mL [amlodipine alone] vs 172.36 ng h/mL [combination], P = 0.389) [geometric mean ratio (GMR) (90% confidence interval [CI]), 1.060 (0.954‐1.178)]. In addition, the exposure of EXP‐3174 was not affected by amlodipine (AUCτ, 1159.46 ng h/mL vs 1105.10 ng h/mL, P = 0.295) (GMR [90% CI], 0.957 [0.891‐1.027]). However, amlodipine significantly decreased the exposure of losartan at steady‐state (AUCτ, 1241.50 ng h/mL vs 1082.02 ng h/mL, P = 0.006) (GMR [90% CI], 0.875 [0.813‐0.942]) and increased oral clearance of losartan (84.65 L/h vs 97.26 L/h, P = 0.002). Combination use of two drugs caused additive haemodynamic changes compared to treatment of amlodipine or losartan alone. The co‐administration of amlodipine and losartan was tolerable and did not cause substantial pharmacokinetic interaction, even though losartan disposition was affected. Combination use of the two drugs caused additive haemodynamic changes compared to monotherapy of amlodipine or losartan. [ABSTRACT FROM AUTHOR]

What is known and objective: Teneligliptin is a DPP‐4 inhibitor used for the treatment of type 2 diabetes mellitus, commonly prescribed in combination with glimepiride. Teneligliptin is metabolized by CYP3A4, and glimepiride might be partly metabolized by CYP3A4. The aim of the study was to investigate the possible effect of glimepiride on the pharmacokinetics of teneligliptin in healthy subjects. Methods: A repeated dose, open‐label, fixed‐sequence study was conducted in 26 healthy subjects. All participants were administered 20 mg teneligliptin daily for 6 days. On day 7, 4 mg glimepiride was administered together with 20 mg teneligliptin. Plasma teneligliptin concentrations were measured at a steady state, and its pharmacokinetic characteristics were compared without and with glimepiride. Results and discussion: No statistically significant difference was found in the effect of glimepiride on teneligliptin pharmacokinetics. The steady‐state Cmax,ss values of teneligliptin without and with glimepiride were 207.01 ng/mL and 202.15 ng/mL, respectively. Its AUCτ values at steady‐state without and with glimepiride were 1527.8 ng · h/mL and 1578.6 ng · h/mL, respectively. The point estimation of geometric mean ratios (GMR) and the 90% confidence interval for both Cmax,ss and AUCτ were within the equivalence range of 0.8‐1.25. The results of the present study revealed that glimepiride did not cause pharmacokinetic interaction with teneligliptin in humans. What is new and conclusion: Glimepiride did not affect the pharmacokinetic characteristics of teneligliptin in healthy subjects. [ABSTRACT FROM AUTHOR]

Purpose: Tamsulosin is one of the most potent drugs currently available to treat benign prostatic hyperplasia. Cytochrome P450 (CYP) 2D6 and CYP3A are the two major enzymes responsible for tamsulosin metabolism. The purpose of this study was to evaluate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on the pharmacokinetics and hemodynamic effects of tamsulosin in humans.Methods: Twenty-nine male subjects were enrolled and their CYP2D6 (*2,*4,*5,*10,*14,*21,*41, and *xN) and CYP3A5 (*5) genotypes were screened. Tamsulosin was administered daily for 6 days to assess its steady-state pharmacokinetics and hemodynamic effects according to CYP2D6 and CYP3A5 genotypes.Results: CYP2D6 group 3 (with genotype *10/*10 or *5/*10) exhibited higher plasma levels than CYP2D6 group 1 (with genotype *1/*1,*1/*2,*1/*2xN, or *2/*10xN) or CYP2D6 group 2 (with genotype *1/*10,*1/*41, or *2/*5) (trough concentrations for groups 1, 2, and 3: 1.3, 1.8, and 3.8 ng/mL, respectively [P < 0.001]; peak concentrations for groups 1, 2, 3: 8.3, 10.0, and 13.8 ng/mL, respectively [P < 0.005]). Similarly, CYP2D6 genotypes influenced the hemodynamic effects of tamsulosin based on systolic and diastolic blood pressures. However, the CYP3A5*3 polymorphism did not affect tamsulosin plasma levels and its hemodynamic effects.Conclusion: The CYP2D6 but not the CYP3A5 genetic polymorphisms affected the pharmacokinetics and the hemodynamic effects of tamsulosin. [ABSTRACT FROM AUTHOR]

Background: Amlodipine, a third-generation dihydropyridine calcium antagonist, is prescribed in the management of angina and hypertension. A newly developed amlodipine formulation (amlodipine camsylate) is associated with similar physical properties, melting point, and solubility—and improved stability against long-term stability test and accelerated temperature test—compared with the conventional formulation (amlodipine besylate).Objective: This study was performed to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of a newly developed amlodipine formulation with a conventional formulation in healthy male subjects.Methods: This randomized, open-label, 2-period crossover comparative study was conducted at the Clinical Trial Center, Gil Medical Center, Gachon Medical School (Incheon, Korea). Eighteen healthy male Korean subjects aged 20 to 40 years were enrolled. All subjects received a single oral dose (5-mg tablet) of a conventional (reference) or newly developed (test) amlodipine formulation. Blood samples for PK analysis of amlodipine were obtained during the 144-hour period after dosing. Systolic and diastolic blood pressure (BP) (SBP and DBP, respectively) and pulse rate (PR) were measured just before each blood sampling. Assessment of safety profiles, including hematology and biochemistry, electrocardiography, urinalysis, and monitoring of adverse events (AEs), was performed.Results: All participants completed both treatment periods. Their mean (SD) age was 22.3 (1.5) years (range, 20–25 years) and their mean (SD) body weight was 67.9 (5.6) kg (range, 57–77 kg). The plasma concentration-time profiles of amlodipine were similar after administration of the 2 formulations. The reference and test formulations were pharmacokinetically equivalent. The 90% CIs for the mean treatment ratios of the log-transformed peak plasma concentration and the area under the plasma concentration-time curve were within the predetermined equivalence range of 80% to 125%. Despite administration of a single dose, significant maximal changes in SBP, DBP, and PR were achieved after drug administration for both formulations compared with baseline values (all, P < 0.001). No significant differences in PD profiles were found between the 2 formulations. No clinically relevant changes were observed in physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study. Neither formulation caused any AEs during the study.Conclusions: The 2 amlodipine formulations were pharmacokinetically equivalent and showed similar PD characteristics in these healthy male subjects. [Copyright &y& Elsevier]

This study aimed to explore pharmacokinetics, pharmacodynamics, and safety/tolerability of MT921, an injectable cholic acid, after a single subcutaneous administration to healthy volunteers. A randomized, double-blinded, placebo-controlled, single dose-ascending phase 1 study enrolled 24 subjects who were assigned to three groups (60 mg, 120 mg, and 150 mg) of MT921. Blood samples were obtained for a 24-h period before and after injecting MT921 to the submental fat area. Plasma concentrations of cholic acid and deoxycholic acid were determined for pharmacokinetic analysis. Levels of free fatty acid, triglyceride, and total cholesterol were measured for pharmacodynamic analysis. Safety and tolerability were assessed until 21 days post-dose. While systemic exposure to cholic acid tended to increase as the MT921 dose increased, pharmacokinetic profiles of deoxycholic acid were similar among dose groups without showing significant changes. Pharmacodynamic profiles were comparable when measured at baseline and post-dose. The most frequent adverse events were injection site pain and edema. All adverse drug reactions resolved without treatment. MT921 appeared to be well-tolerated after an injection to the submental area at a dose up to 150 mg. Systemic exposure to cholic acid increased as the dose increased. Blood lipid profiles and deoxycholic acid levels were not affected by MT921 treatment. [ABSTRACT FROM AUTHOR]

Abstract: Background: Various cytochrome P450 isoforms modulate sibutramine activity and influence sibutramine plasma levels and pharmacokinetics. However, there are no available data to demonstrate the association of these polymorphisms with the clinical outcomes of sibutramine administration. Methods: This study was a sub-investigation of a 12-week, double-blind, placebo-controlled trial examining the additive effect of orlistat on sibutramine. The final analysis was restricted to 101 women who had fulfilled the protocol. We evaluated the effects of genetic polymorphisms of CYP3A5, CYP2C19 and CYP2B6 on the % weight loss and the occurrence of adverse events. Results: The change of pulse rate from baseline value was affected by both CYP2B6 and CYP3A5 genetic polymorphisms (P <.01 for CYP3A5 and P =.01 for CYP2B6). Both CYP2B6 and CYP3A5 showed gene–gene interactions (P <.01). After adjusting for significant variables in the backward stepwise regression model, the change of pulse rate and time-dependent weight reduction were significant only among the CYP2B6 genotypes (P =.027 and P <.01, respectively). Conclusion: The CYP2B6*6 allele influences the extent of weight reduction and pulse rate changes in patients undergoing sibutramine treatment. [Copyright &y& Elsevier]