title: Pharmacokinetic and Pharmacodynamic Comparison of Sildenafil-Bosentan and Sildenafil-Ambrisentan Combination Therapies for Pulmonary Hypertension.
abstract: To elucidate whether the pharmacokinetics (PK) and pharmacodynamics (PD) of sildenafil are influenced differently when it is coadministered with bosentan (S+B) or with ambrisentan (S+A), we evaluated the PK and PD profiles of sildenafil before and after 4-5 weeks of S+A or S+B treatment in patients with pulmonary arterial hypertension. The area under the plasma concentration-time curve of sildenafil was significantly higher in S+A treatment than in S+B treatment (165.8 ng•h/mL vs. 396.8 ng•h/mL, P = 0.018) and the oral clearance of sildenafil was significantly lower after S+A treatment than after S+B treatment (120.6 L/h/kg vs. 50.4 L/h/kg, P = 0.018). In the PD study, incremental shuttle walking distance was superior during treatment with S+A than during treatment with S+B (S+B; 280 m vs. S+A; 340 m, P = 0.042). There were no concerns about safety with either combination therapy regime.
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Hakamata
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Odagiri
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyakawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Irisawa
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Inui
authors.affiliation: Department of Pharmacy Practice and Science, School of Pharmaceutical Science, University of Shizuoka, Shizuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Pharmacy Practice and Science, School of Pharmaceutical Science, University of Shizuoka, Shizuoka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D000077300:Bosentan; D004359:Drug Therapy, Combination; D015444:Exercise; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D011724:Pyridazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D000068677:Sildenafil Citrate / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D010666:Phenylpropionates; D011724:Pyridazines; D013449:Sulfonamides; D000068677:Sildenafil Citrate; C467894:ambrisentan; D000077300:Bosentan