Glomerular filtration, pharmacokinetics studies

Lenalidomide was approved recently for the indication of myelodysplastic syndrome where the 5q deletion is present. Since lenalidomide is an analog of thalidomide, all the same precautions must be taken to prevent phocomelia. The time to maximum lenalidomide concentrations occurs 0.5 to 4 hours after the dose. The terminal half-life ranges from 3 to 9 hours. Approximately 65% of lenalidomide is eliminated unchanged in the urine, with clearance exceeding the glomerular filtration rate. To date, no pharmacokinetic studies have been done in patients with renal dysfunction. Lenalidomide is used in the treatment of myelodysplastic syndrome and multiple myeloma. Other side effects are neutropenia, thrombocytopenia, deep vein thrombosis, and pulmonary embolus. 

A study in 16 healthy subjects found that indometacin 100 mg twice daily for 9 days reduced the maximum blood levels of a single 300-mg dose of ciclosporin by 18% and slowed its absorption (time to maximum concentration increased by 30 minutes) but the extent of absorption was not changed, indicating the absence of a clinically relevant pharmacokinetic interaction. Further, the pharmacokinetics of indometacin were not affected by ciclosporin. A study in rheumatoid arthritis patients taking ciclosporin 2.5 mg/kg daily, found that creatinine clearances were reduced by 6% in those taking indometacin 50 mg four times daily, but this was not considered to be clinically important. An experimental study in healthy subjects found that ciclosporin 10 mg/kg twice daily for 4 days had no effect on effective renal plasma flow (ERPF) or the glomerular filtration rate (GFR), but when indometacin 50 mg twice daily was added the ERPF fell by 32% and the GFR by 37%. ... 

In contrast to the naturally occurring Gd compounds, pharmacokinetic and pharmacological properties of the element s DOTA and DTPA chelates that are used in MRl have been studied more intensively. From a kinetic point of view, these highly hydrophilic compounds behave in an identical fashion. As expected from hydrophilic substances, the volume of distribution is small being 0.17 0.01 liters/kg in humans [13] while the plasma elimination half-life is around 20 and 90 min in rats and humans, respectively [4]. In mice 89% of the administered Gd-DOTA and Gd-DTPA doses was recovered in the urine within 1 hr [14]. In correlation with the reduced GFR in patients with chronic renal failure (median creatinine clearance 25.5 mL/min) the serum half-life of Gd-DTPA was prolonged and the renal clearance decreased. Recovery of the Gd-DTPA after administration of a 0.1 mmol/kg dose was 92 12%, whereas extrarenal elimination in these subjects accounted for less than 0.4% [15], indicating that glomerular filtration is the predominant route of elimination of the chelates. 

Seddon et al. (1980) studied the pharmacokinetics of ceftriaxone in humans (Table XII). Six male volunteers received a 500-mg intravenous bolus injection of ceftriaxone. Mean serum concentrations of 93 p,g/ml were measured 10 min after dosing. After a rapid distribution phase, the elimination half-life was 8.8 hr. Total urinary recovery after 48 hr was 58% the remainder was eliminated via biliary secretion. Metabolism is minimal. The serum clearance of ceftriaxone is only about 1% of the glomerular filtration rate, suggesting that there is no tubular secretion of this drug. Wise et al. (1980c) reported that ceftriaxone was 95% protein bound in humans. 

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