High inter-individual variability of vardenafil pharmacokinetics in patients with pulmonary hypertension.
OBJECTIVE
To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH).


METHODS
Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis.


RESULTS
The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t(max)) of 1 h and a mean elimination half-life (t(1/2)) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C(max)) was 21.4 ± 1.7 μg/L, (2) the normalized C(max) (C(max, norm)) 79.1 ± 1.6 g/L, (3) the area under the time-concentration curve (AUC) 71.5 ± 1.6 μg · h/L and (4) the normalized AUC (AUC(norm)) 261.6 ± 1.7 g · h/L. Patients co-medicated with bosentan reached t(max) later and had a 90% reduction of C(max), C(max, norm), AUC and AUC(norm).


CONCLUSIONS
The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted.
Division of Clinical Pharmacology, Department of Pharmacology and Clinical Neuroscience, Umeå University and Umeå University Hospital, 901 85 Umeå, Sweden. anna.sandqvist@pharm.umu.se
A M
AM
Sandqvist
D
D
Henrohn
J
J
Schneede
M
M
Hedeland
H C
HC
Egeröd
U G
UG
Bondesson
B G
BG
Wikström
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics*; D013450:Sulfones / Q000097:blood / Q000493:pharmacokinetics; D014227:Triazines / Q000097:blood / Q000493:pharmacokinetics; D000069058:Vardenafil Dihydrochloride; D014665:Vasodilator Agents / Q000097:blood / Q000493:pharmacokinetics*
D007093:Imidazoles; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D013450:Sulfones; D014227:Triazines; D014665:Vasodilator Agents; D000069058:Vardenafil Dihydrochloride