Steady state pharmacokinetics and dose equivalents of oral clodronate in renal failure.
OBJECTIVE
Clodronate is used in the treatment of osteoporosis, and malignancy-associated bone disease. The steady state pharmacokinetics and the dose equivalents of oral clodronate were assessed in subjects with various degrees of renal failure.


METHODS
1,600 mg of clodronate was given orally mornings for 11 days to 14 healthy volunteers (creatinine clearance, CLCr, > 80 ml/min), and 18, 12 and 16 subjects with mild (50 - 80 ml/min), moderate (30 - 50 ml/min) and severe (< 30 ml/min) renal failure, respectively. Trough drug levels at 4, 7 and 11 days, and concentration-time curves for 72 h after the last dose were followed.


RESULTS
In all study groups, the trough drug levels achieved the kinetic steady state within 11 days. The area under the 24-h concentration-time curve (AUC0-24) enlarged and the elimination half-life (t1/2elim) prolonged progressively when the renal function was impaired. The maximum drug level and the time to maximum were not changed significantly in the renal failure. In the steady state phase, the diurnal drug excretion (E0-24) was not changed by the kidney function, but the renal drug clearance (CLD) decreased in close correlation with CLCr. The normal-to-failed AUC0-24 ratios in mild, moderate, and severe renal failure were 0.53, 0.43 and 0.31, respectively, when the ideally-matched counterpart was assumed as the normal reference to each renal failure group.


CONCLUSIONS
In mild, moderate and severe renal failure, 53%, 43% and 31% oral clodronate doses, respectively, resulted in drug AUCs similar to those in controls with normal (> 80 ml/min) CLCR.
Department of Internal Medicine, Tampere University Hospital, Tampere, Finland. satu.marjo.makela@uta.fi
S
S
Mäkelä
H
H
Saha
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I
Ala-Houhala
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S
Liukko-Sipi
P
P
Ylitalo
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001682:Biological Availability; D050071:Bone Density Conservation Agents / Q000493:pharmacokinetics*; D004002:Clodronic Acid / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000378:metabolism*
D050071:Bone Density Conservation Agents; D004002:Clodronic Acid