CYP2C19 Genotype-Dependent Pharmacokinetic Drug Interaction Between Voriconazole and Ritonavir-Boosted Atazanavir in Healthy Subjects
© 2016, The American College of Clinical Pharmacology..
Voriconazole, a broad-spectrum triazole antifungal agent, is metabolized by cytochrome P450 (CYP) 2C19 and, to a lesser extent, by CYP3A. Genetic polymorphism of CYP2C19 not only plays a prominent role in its disposition but may also influence potential drug interactions with CYP450 modulators such as ritonavir. This study assessed 2-way drug interactions of voriconazole added on to ritonavir-boosted atazanavir in both CYP2C19 extensive-metabolizer (EM) and poor-metabolizer (PM) healthy subjects. Each subject received voriconazole alone on days 1-3, followed by a 7-day washout. Atazanavir/ritonavir 300/100 mg once daily was given on days 11-30 and voriconazole on days 21-30. Voriconazole doses were 200 mg (400 mg on days 1 and 21) twice daily and 50 mg (100 mg on days 1 and 21) twice daily for CYP2C19 EM and PM subjects, respectively. On coadministration, voriconazole AUC and Cmin decreased by 33% (90%CI, 22%-42%) and 39% (90%CI, 28%-49%), respectively, in CYP2C19 EMs, whereas voriconazole Cmax and AUC increased 4.4-fold (90%CI, 3.6-fold to 5.4-fold) and 5.6-fold (90%CI, 4.5-fold to 7.0-fold), respectively, in PMs. Adding voriconazole resulted in a 20%-30% decrease in atazanavir Cmin in both EMs and PMs. Ritonavir exposure was generally unchanged in either population. The safety and tolerability profiles of the combination were comparable with atazanavir/ritonavir and voriconazole administered alone. The most frequent adverse events with voriconazole were visual disturbance and headache. Coadministration of voriconazole and atazanavir/ritonavir is not recommended unless the benefit/risk to the patient justifies the use of the combination.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2017 |
|---|---|
| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:57 |
|---|---|
| Enthalten in: |
Journal of clinical pharmacology - 57(2017), 2 vom: 15. Feb., Seite 235-246 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zhu, Li [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 16.08.2017 Date Revised 27.11.2017 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1002/jcph.798 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM262566818 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM262566818 | ||
| 003 | DE-627 | ||
| 005 | 20231224202033.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2017 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1002/jcph.798 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0875.xml |
| 035 | |a (DE-627)NLM262566818 | ||
| 035 | |a (NLM)27432796 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zhu, Li |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a CYP2C19 Genotype-Dependent Pharmacokinetic Drug Interaction Between Voriconazole and Ritonavir-Boosted Atazanavir in Healthy Subjects |
| 264 | 1 | |c 2017 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 16.08.2017 | ||
| 500 | |a Date Revised 27.11.2017 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2016, The American College of Clinical Pharmacology. | ||
| 520 | |a Voriconazole, a broad-spectrum triazole antifungal agent, is metabolized by cytochrome P450 (CYP) 2C19 and, to a lesser extent, by CYP3A. Genetic polymorphism of CYP2C19 not only plays a prominent role in its disposition but may also influence potential drug interactions with CYP450 modulators such as ritonavir. This study assessed 2-way drug interactions of voriconazole added on to ritonavir-boosted atazanavir in both CYP2C19 extensive-metabolizer (EM) and poor-metabolizer (PM) healthy subjects. Each subject received voriconazole alone on days 1-3, followed by a 7-day washout. Atazanavir/ritonavir 300/100 mg once daily was given on days 11-30 and voriconazole on days 21-30. Voriconazole doses were 200 mg (400 mg on days 1 and 21) twice daily and 50 mg (100 mg on days 1 and 21) twice daily for CYP2C19 EM and PM subjects, respectively. On coadministration, voriconazole AUC and Cmin decreased by 33% (90%CI, 22%-42%) and 39% (90%CI, 28%-49%), respectively, in CYP2C19 EMs, whereas voriconazole Cmax and AUC increased 4.4-fold (90%CI, 3.6-fold to 5.4-fold) and 5.6-fold (90%CI, 4.5-fold to 7.0-fold), respectively, in PMs. Adding voriconazole resulted in a 20%-30% decrease in atazanavir Cmin in both EMs and PMs. Ritonavir exposure was generally unchanged in either population. The safety and tolerability profiles of the combination were comparable with atazanavir/ritonavir and voriconazole administered alone. The most frequent adverse events with voriconazole were visual disturbance and headache. Coadministration of voriconazole and atazanavir/ritonavir is not recommended unless the benefit/risk to the patient justifies the use of the combination | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a HIV/AIDS | |
| 650 | 4 | |a clinical pharmacology (CPH) | |
| 650 | 4 | |a drug-drug interactions | |
| 650 | 4 | |a pharmacogenetics/pharmacogenomics | |
| 650 | 4 | |a pharmacokinetics and drug metabolism | |
| 650 | 7 | |a Antifungal Agents |2 NLM | |
| 650 | 7 | |a Drug Combinations |2 NLM | |
| 650 | 7 | |a HIV Protease Inhibitors |2 NLM | |
| 650 | 7 | |a Atazanavir Sulfate |2 NLM | |
| 650 | 7 | |a 4MT4VIE29P |2 NLM | |
| 650 | 7 | |a CYP2C19 protein, human |2 NLM | |
| 650 | 7 | |a EC 1.14.14.1 |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 CYP2C19 |2 NLM | |
| 650 | 7 | |a EC 1.14.14.1 |2 NLM | |
| 650 | 7 | |a Voriconazole |2 NLM | |
| 650 | 7 | |a JFU09I87TR |2 NLM | |
| 650 | 7 | |a Ritonavir |2 NLM | |
| 650 | 7 | |a O3J8G9O825 |2 NLM | |
| 700 | 1 | |a Brüggemann, Roger J |e verfasserin |4 aut | |
| 700 | 1 | |a Uy, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Colbers, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Hruska, Matthew W |e verfasserin |4 aut | |
| 700 | 1 | |a Chung, Ellen |e verfasserin |4 aut | |
| 700 | 1 | |a Sims, Karen |e verfasserin |4 aut | |
| 700 | 1 | |a Vakkalagadda, Blisse |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Xiaohui |e verfasserin |4 aut | |
| 700 | 1 | |a van Schaik, Ron H N |e verfasserin |4 aut | |
| 700 | 1 | |a Burger, David M |e verfasserin |4 aut | |
| 700 | 1 | |a Bertz, Richard J |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of clinical pharmacology |d 1973 |g 57(2017), 2 vom: 15. Feb., Seite 235-246 |w (DE-627)NLM000005576 |x 1552-4604 |7 nnns |
| 773 | 1 | 8 | |g volume:57 |g year:2017 |g number:2 |g day:15 |g month:02 |g pages:235-246 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1002/jcph.798 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 57 |j 2017 |e 2 |b 15 |c 02 |h 235-246 | ||