Intravenous and subcutaneous weight-based dosing of the low molecular weight heparin tinzaparin (Innohep) in end-stage renal disease patients undergoing chronic hemodialysis.
BACKGROUND
Patients with end-stage renal disease are subject to a broad range of thrombotic complications. Low molecular weight heparins (LMWHs) are effective antithrombotic agents; however, they are cleared largely by renal mechanisms, raising uncertainty about their use in renally impaired patients.


METHODS
Twelve chronic hemodialysis subjects were administered two single doses of the LMWH tinzaparin, 75 IU/kg, 2 weeks apart: subcutaneously (SC) on an off-dialysis day and intravenously (IV) just before dialysis.


RESULTS
Mean maximal anti-factor Xa (anti-Xa) activity was 0.33 IU/mL 4.0 hours after SC administration and 1.33 IU/mL 0.25 hours after IV administration. Anti-Xa half-lives were 3.89 and 2.31 hours, respectively. Anti-Xa activity returned to baseline within 24 hours of administration by either route. Consistent with population pharmacokinetic analyses of clinical study subjects with severe renal impairment, anti-Xa clearance after tinzaparin administration was reduced 28% relative to subjects with normal renal function. All 12 study subjects completed hemodialysis without requiring additional anticoagulation. One subject had minimal clotting in the dialyzer drip chamber, and one subject had mild prolonged bleeding at the vascular access site after dialysis needle removal. No major bleeding events occurred.


CONCLUSIONS
Tinzaparin, 75 IU/kg, SC on an off-dialysis day and IV just before dialysis is well tolerated in chronic hemodialysis patients. The weight-based regimen of 75 IU/kg IV just before dialysis provides adequate anticoagulation. SC weight-based dosing on off-dialysis days is a feasible regimen for further clinical thromboprophylaxis efficacy studies in hemodialysis patients. The risk for clinical overdose in severely renally impaired patients using this weight-based regimen of tinzaparin is unlikely.
Bristol-Myers Squibb Pharma Company, Wilmington, DE, USA. james.hainer@astrazeneca.com
James W
JW
Hainer
Donald J
DJ
Sherrard
Suzanne K
SK
Swan
Jeffrey S
JS
Barrett
Christopher A
CA
Assaid
Michael J
MJ
Fossler
Donna S
DS
Cox
Robert M
RM
Williams
Amy L
AL
Pittenger
Carol A
CA
Stephenson
Tsushung A
TA
Hua
D000293:Adolescent; D000328:Adult; D000368:Aged; D000990:Antithrombin III / Q000037:antagonists & inhibitors / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects; D018592:Cross-Over Studies; D004244:Dizziness / Q000139:chemically induced; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D006261:Headache / Q000139:chemically induced; D006470:Hemorrhage / Q000139:chemically induced; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000628:therapy*; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D011446:Prospective Studies; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D000078222:Tinzaparin; D016896:Treatment Outcome
D015415:Biomarkers; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D000078222:Tinzaparin; D000990:Antithrombin III; D013917:Thrombin