Evaluation of Renal Impairment Influence on Metabolic Drug Clearance using a Modelling Approach

Tuloup, Vianney; Goutelle, Sylvain; Tod, Michel; Bourguignon, Laurent

doi:10.1007/s40262-022-01205-3

Cited by 2 publications

(6 citation statements)

References 67 publications

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“…Thus, the study population was a limited pool from one study site and differences with regard to, for example, demographics and individual health have to be expected from the wider population and individuals with CKD. Generally, CKD may alter not only renal drug elimination but also hepatic metabolism via multiple uremic components 24 . There is a paucity of clinical data on the relationship between severity of CKD and potential changes in CYP3A4‐mediated clearance for drugs primarily eliminated via this pathway 25 .…”

Section: Discussionmentioning

confidence: 99%

“…End‐stage renal disease has been found to have direct inhibitory effects on CYP3A4 activity that were described as small 26 . In a model analysis including a set of CYP3A4 substrates, observed changes in CYP3A4 substrate AUC were limited to about twofold in severe renal impairment 24 . Renal impairment data specific to ethinyl estradiol and levonorgestrel are not available according to the drug label 27 .…”

Section: Discussionmentioning

confidence: 99%

“…Generally, CKD may alter not only renal drug elimination but also hepatic metabolism via multiple uremic components. 24 There is a paucity of clinical data on the relationship between severity of CKD and potential changes in CYP3A4-mediated clearance for drugs primarily eliminated via this pathway. 25 End-stage renal disease has been found to have direct inhibitory effects on CYP3A4 activity that were described as small.…”

Section: Articlementioning

confidence: 99%

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Zibotentan Can Be Co‐administered with Contraceptives Containing Ethinyl Estradiol and Levonorgestrel: A Pharmacokinetic Drug–Drug Interaction Study

Mercier,

Kois,

Karsanji

et al. 2024

Clin Pharma and Therapeutics

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The endothelin A receptor antagonist zibotentan, combined with the sodium‐glucose co‐transporter‐2 inhibitor dapagliflozin, is being investigated for the treatment of chronic kidney disease with high proteinuria. To allow women of childbearing potential access to this treatment, highly effective contraception is required and drug interactions compromising contraception reliability must be avoided. This study investigated the risk of pharmacokinetic (PK) interaction between zibotentan and the contraceptives ethinyl estradiol and levonorgestrel. A single‐sequence, within‐participant comparison study was conducted in 24 healthy women of non‐childbearing potential, comparing the PK of ethinyl estradiol/levonorgestrel alone and with zibotentan. Single oral doses of 0.06 mg ethinyl estradiol/0.3 mg levonorgestrel were administered on Days 1 and 15; zibotentan 10 mg was dosed orally, once‐daily through Days 6–19. PK profiles were determined and ethinyl estradiol/levonorgestrel PK was compared between Day 1 and 15 based on geometric least‐squares mean ratios of PK parameters, including maximum observed concentration (Cmax) and area under the plasma concentration–time curve from zero to infinity (AUCinf). Co‐administration with zibotentan did not affect ethinyl estradiol PK (geometric mean ratio [90% confidence interval] Cmax 1.05 [0.99–1.11], AUCinf 1.00 [0.96–1.05]), while a weak interaction (increased exposure) was observed for levonorgestrel (Cmax 1.12 [1.02–1.23], AUCinf 1.30 [1.21–1.39]), which was regarded as without clinical relevance. Plasma exposure of ethinyl estradiol/levonorgestrel was not reduced by multiple‐dose zibotentan. In conclusion, contraception containing ethinyl estradiol/levonorgestrel is regarded possible under zibotentan‐containing treatments. This expands choices for women of childbearing potential, supporting diversity in the ZENITH High Proteinuria trial.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Articlementioning

confidence: 99%

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Zibotentan Can Be Co‐administered with Contraceptives Containing Ethinyl Estradiol and Levonorgestrel: A Pharmacokinetic Drug–Drug Interaction Study

Mercier,

Kois,

Karsanji

et al. 2024

Clin Pharma and Therapeutics

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“…Severe renal impairment may also impact selected cytochrome P450 pathways including 3A4 18 . Thus, agents that are primarily eliminated in the liver may have reduced elimination in severe renal impairment.…”

Section: Look At the Big Picture And Avoid Practicing In A Silomentioning

confidence: 99%

“…17 Severe renal impairment may also impact selected cytochrome P450 pathways including 3A4. 18 Thus, agents that are primarily eliminated in the liver may have reduced elimination in severe renal impairment. As noted above in renal failure, phases of liver injury can occur, and should be watched and drug doing assessed accordingly.…”

Section: Disease Relatedmentioning

confidence: 99%

Developing precision‐based multidisciplinary pharmacotherapy management plans in the critically ill

Dager

2023

Pharmacotherapy

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Evaluation of Renal Impairment Influence on Metabolic Drug Clearance using a Modelling Approach

Cited by 2 publications

References 67 publications

Zibotentan Can Be Co‐administered with Contraceptives Containing Ethinyl Estradiol and Levonorgestrel: A Pharmacokinetic Drug–Drug Interaction Study

Zibotentan Can Be Co‐administered with Contraceptives Containing Ethinyl Estradiol and Levonorgestrel: A Pharmacokinetic Drug–Drug Interaction Study

Developing precision‐based multidisciplinary pharmacotherapy management plans in the critically ill

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