Determining the optimal dose of atrasentan by evaluating the exposure-response relationships of albuminuria and bodyweight

Jeroen V Koomen, Jasper Stevens, Nael M Mostafa, Hans-Henrik Parving, Dick de Zeeuw, Hiddo J L Heerspink

OnderzoeksoutputAcademicpeer review

10 Citaten (Scopus)
248 Downloads (Pure)

Samenvatting

This study aimed to identify the optimal dose of the endothelin-1 receptor antagonist atrasentan with maximal albuminuria reduction and minimal signs of sodium retention, as manifested by increase in bodyweight. Data from the RADAR-JAPAN studies were used, evaluating the effect of 0.75 or 1.25 mg/d of atrasentan in 161 patients with type 2 diabetes and kidney disease. Individual pharmacokinetic parameters were estimated using a population pharmacokinetic approach. Subsequently, changes in the urinary albumin-to-creatinine ratio (UACR) and bodyweight from baseline after 2 weeks' exposure were modelled as a function of the pharmacokinetic parameters. The 0.75 and 1.25 mg doses showed a mean UACR reduction of 34.0% and 40.1%, whereas mean bodyweight increased by 0.9 and 1.1 kg, respectively. A large variation between individuals was observed in the UACR and bodyweight responses. Individual pharmacokinetic parameters correlated significantly with both individual UACR and bodyweight responses (P < .01). The individual response curves for UACR and bodyweight crossed at approximately the mean trough concentration of 0.75 mg atrasentan, indicating that 0.75 mg/d of atrasentan is the optimal dose for kidney protection with maximal efficacy (albuminuria reduction) and safety (minimal sodium retention).

Originele taal-2English
Pagina's (van-tot)2019-2022
Aantal pagina's4
TijdschriftDiabetes obesity & metabolism
Volume20
Nummer van het tijdschrift8
DOI's
StatusPublished - aug.-2018

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