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415
Pharmacokinetics of Tenofovir Exalidex (TXL) in
Severe Renal Impairment: No Need for Dosage
Adjustment
Michael Snyder, Jenel Cobb, Carlos Canizares, Theresa
Matkovits and Robert Foster, Contravir Pharmaceuticals Inc.
Background: Tenofovir exalidex (TXL) is a novel tenofovir
(TFV) prodrug designed to achieve high hepatic concentrations
of TFV while reducing peripheral TFV concentrations. Antiviral
activity of TXL at doses between 50 mg and 100 mg QD
were comparable to TDF, while TXL-derived TFV exposure
was about 10-fold less compared to post-TDF. As TFV is
eliminated renally, a study in subjects with severe renal
impairment (RI) was conducted to further define the safety
profile and pharmacokinetics (PK) of TXL. The objective of
the study was to compare plasma and urine PK of TXL and
TFV, after TXL administration in subjects with severe renal
impairment versus healthy controls. Methods: This was a
phase I open-label study of eight subjects with severe renal
impairment (eGFR < 30 mL/min/1.73m2, not on dialysis) and
8 healthy subjects, matched for sex, age and BMI. Each
subject received a single oral dose of TXL 50 mg. Blood and
urine samples were collected pre-dose and up to 6 days postdosing.
Plasma and urine concentrations of TXL and TFV
were quantitated by LC-MS/MS and PK was determined using
non-compartmental analysis. Results: 16 subjects completed
the study and a pharmacokinetic and statistical analysis was
performed to compare RI versus healthy subjects. Based on
the geometric mean ratios (GMR) of the TXL PK parameters,
there was a 3.50% and a 13.23% increase in AUC0-inf and
Cmax, respectively, for subjects with severe RI. There were no
detectable levels of TXL excreted in urine following a single
oral 50 mg dose of TXL in healthy subjects or in subjects with
severe RI. Based on the GMR of the TFV PK parameters, a
1170% and a 442% increase in AUC0-inf and Cmax, respectively,
for subjects with severe RI. Despite an increase TFV exposure
in RI subjects, exposures were comparable to that observed
after TDF 300mg, indicating no dosage adjustment of TXL
is required. TFV renal clearance in subjects with severe RI
was lower than in healthy subjects (mean CLr = 2.15 L/hr vs
14.2 L/hr). In both groups, renal clearance was higher than
eGFR suggesting that active tubular secretion contributes
to TFV renal clearance in addition to glomerular filtration.
Conclusion: Since TFV exposure is strongly correlated to
eGFR values, TFV exposure following 50 mg TXL is expected
to be lower in mild and moderate renal impairment than
observed in this study of severely renally impaired subjects.
Dosage adjustment is not necessary for subjects with severe
RI receiving TXL.
Disclosures:
Theresa Matkovits – ContraVir: Employment
Robert Foster – ContraVir Pharmaceuticals Inc.: Employment
Disclosure information not available at the time of publication: Michael Snyder,
Jenel Cobb, Carlos Canizares |
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发表于 2018-10-18 13:51
