Pharmacokinetics, safety and tolerance of voriconazole in renally impaired subjects: two prospective, multicentre, open-label, parallel-group volunteer studies.
OBJECTIVE
Since little is known regarding the pharmacokinetics of voriconazole in renally impaired patients, two prospective, open-label, parallel-group volunteer studies were conducted to estimate the effect of renal impairment on the pharmacokinetics of oral voriconazole and intravenous voriconazole solubilized with sulphobutylether-beta-cyclodextrin (SBECD), respectively.


METHODS
In study A, male subjects with no (n = 6), mild (n = 6), moderate (n = 6) or severe (n = 6) renal impairment received one 200 mg dose of oral voriconazole. Voriconazole plasma levels were periodically assessed until 48 hours post-dose. In study B, male subjects with no (n = 6) or moderate (n = 7) renal impairment received multiple doses of intravenous voriconazole solubilized with SBECD (6 mg/kg twice daily [day 1] then 3 mg/kg twice daily [days 2-6] followed by a final dose of 3 mg/kg on the morning of day 7) at an infusion rate of 3 mg/kg/h. Voriconazole plasma levels were periodically assessed until 36 hours following the final dose. Pharmacokinetics were determined by non-compartmental methods.


RESULTS
The pharmacokinetics of voriconazole were unaffected in subjects with any degree of renal impairment in both studies. In study B, clearance of SBECD was proportional to creatinine clearance (r2 = 0.857). Although two subjects had >30% increase in serum creatinine from baseline, these changes did not correlate with SBECD trough levels (r2 = 0.053). The majority of subjects with moderate renal insufficiency were able to tolerate 7 days of intravenous voriconazole solubilized with SBECD.


CONCLUSIONS
These data suggest that renal impairment does not affect the pharmacokinetics of voriconazole. Furthermore, in subjects with moderate renal impairment, there is a strong linear correlation between SBECD clearance and creatinine clearance, and elevated SBECD levels do not necessarily correlate with increased serum creatinine levels (an indicator of worsening renal function).
Abel
Samantha
S
Pfizer Global Research and Development, Sandwich, UK.
Allan
Richard
R
Gandelman
Kuan
K
Tomaszewski
Konrad
K
Webb
David J
DJ
Wood
Nolan D
ND
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003404:Creatinine / Q000097:blood / Q000652:urine; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D051437:Renal Insufficiency; D012720:Severity of Illness Index; D012995:Solubility; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D065819:Voriconazole; D047392:beta-Cyclodextrins / Q000737:chemistry
D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D047392:beta-Cyclodextrins; C093196:SBE4-beta-cyclodextrin; D003404:Creatinine; D065819:Voriconazole