Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran.
BACKGROUND
Ximelagatran is an oral direct thrombin inhibitor currently in clinical development as an anticoagulant for the prevention and treatment of thromboembolic disease. After oral administration, ximelagatran is rapidly absorbed and bioconverted to its active form, melagatran.


OBJECTIVE
To investigate the effect of severe renal impairment on the pharmacokinetics and pharmacodynamics of melagatran following administration of subcutaneous melagatran and oral ximelagatran.


METHODS
This was a nonblinded randomised crossover study with 2 study days, separated by a washout period of 1-3 weeks. Twelve volunteers with severe renal impairment and 12 controls with normal renal function were included, with median (range) glomerular filtration rates (GFR) of 13 (5-24) and 86 (70-105) mL/min, respectively. All volunteers received, in a randomised sequence, a 3mg subcutaneous injection of melagatran and a 24mg immediate-release tablet of ximelagatran. Blood samples were collected up to 12 and 14 hours after administration of the subcutaneous and oral doses, respectively, for determination of melagatran plasma concentrations and the activated partial thromboplastin time (APTT), an ex vivo measurement of coagulation time. Urine was collected for 24 hours after each dose for determination of melagatran concentration.


RESULTS
For the volunteers with severe renal impairment, the area under the plasma concentration-time curve (AUC) and the half-life of melagatran were significantly higher than in the control group with normal renal function. Least-squares mean estimates of the ratios of the mean AUC for volunteers with severe renal impairment and controls (95% confidence intervals) were 4.03 (3.29-4.93) after subcutaneous melagatran and 5.33 (3.76-7.56) after oral ximelagatran. This result was related to the decreased renal clearance (CL(R)) of melagatran, which was linearly correlated with GFR. In the severe renal impairment and control groups, respectively, the mean CL(R) of melagatran was 12.5 and 81.3 mL/min after subcutaneous administration of melagatran and 14.3 and 107 mL/min after oral administration of ximelagatran. There was a nonlinear relationship between the APTT ratio (postdose/predose APTT value) and melagatran plasma concentration. A statistically significant higher slope of the concentration-effect relationship, described by linear regression of the APTT ratio versus the square root of melagatran plasma concentrations, was estimated for the group with severe renal impairment compared to the control group; however, the increase in slope was minor and the estimated differences in APTT ratio between the groups in the studied concentration range was less than 10% and not considered clincially relevant. Ximelagatran and melagatran were well tolerated in both groups.


CONCLUSIONS
After administration of subcutaneous melagatran and oral ximelagatran, subjects with severe renal impairment had significantly higher melagatran exposure and longer half-life because of lower CL(R) of melagatran compared with the control group with normal renal function, suggesting that a decrease in dose and/or an increase in the administration interval in patients with severe renal impairment would be appropriate.
Eriksson
Ulf G
UG
Experimental Medicine, AstraZeneca R&D, Mölndal, Sweden. ulf.eriksson@astrazeneca.com
Johansson
Susanne
S
Attman
Per-Ola
PO
Mulec
Henrik
H
Frison
Lars
L
Fager
Gunnar
G
Samuelsson
Ola
O
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001384:Azetidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001596:Benzylamines; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007279:Injections, Subcutaneous; D019934:International Normalized Ratio; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics*; D013917:Thrombin / Q000037:antagonists & inhibitors; D013997:Time Factors
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D011355:Prodrugs; C109573:melagatran; C426686:ximelagatran; D013917:Thrombin; D005998:Glycine