The effect of diurnal variation, CYP2B6 genotype, and age on the pharmacokinetics of nevirapine in African Children
<h4>Objective</h4> <p>We aimed to characterise the effects of CYP2B6 polymorphisms, diurnal variation, and demographic factors on nevirapine pharmacokinetics in African children.</p> <h4>Methods</h4> <p>Nonlinear mixed-effects modelling conducted in NONMEM...
| Главные авторы: | , , , , , , , , , , , |
|---|---|
| Формат: | Journal article |
| Опубликовано: |
Oxford University Press
2016
|
| _version_ | 1826286842361675776 |
|---|---|
| author | Bienczak, A Cook, A Wiesner, L Mulenga, V Kityo, C Kekitiinwa, A Walker, A Owen, A Gibb, D Burger, D McIlleron, H Denti, P |
| author_facet | Bienczak, A Cook, A Wiesner, L Mulenga, V Kityo, C Kekitiinwa, A Walker, A Owen, A Gibb, D Burger, D McIlleron, H Denti, P |
| author_sort | Bienczak, A |
| collection | OXFORD |
| description | <h4>Objective</h4> <p>We aimed to characterise the effects of CYP2B6 polymorphisms, diurnal variation, and demographic factors on nevirapine pharmacokinetics in African children.</p> <h4>Methods</h4> <p>Nonlinear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration-time data from 414 children aged 0.3–15 years. </p> <h4>Results</h4> <p>Nevirapine pharmacokinetics was best described using a 1-compartmental disposition model with elimination through a well-stirred liver model accounting for first-pass effect and transit-compartment absorption. Intrinsic clearance was affected by diurnal variation (characterised using a cosine function with peak amplitude 29% at 12 noon) and CYP2B6 metaboliser status (extensive [EM] 516GG|983TT, reference; intermediate [IM] 516GT|983TT or 516GG|983TC, 17% lower; slow [SM] 516TT|983TT or 516GT|983TC, 50% lower; ultra-slow [USM] 516GG|983CC, 68% lower). Age was found to affect pre-hepatic bioavailability: 31.7% lower at birth and increasing exponentially. Median (90% CI) evening Cmin in the different metaboliser groups were 5.01 (3.01-7.47), 6.55 (3.65-13.32), 11.59 (5.44-22.71), and 12.32 (12.32-27.25) mg/L, respectively. Evening Cmin were <3mg/L in 43% of EM <6kg and 26% of IM <6kg, while 73% of SM and 88% USM in all weight-bands had evening Cmin >8 mg/L. Cmin was not markedly affected by administration time but by unequal splitting of the daily dose.</p> <h4>Conclusions</h4> <p>Diurnal variation does not greatly affect nevirapine exposure. However, when daily doses cannot be split equally, the larger dose should be given in the morning. To achieve homogeneous exposures, nevirapine doses for SM and USM should be reduced by 50%, and children <6kg with EM or IM metabolizer status should receive the same dose as children weighing 6-10 kg.</p> |
| first_indexed | 2024-03-07T01:49:43Z |
| format | Journal article |
| id | oxford-uuid:99a80c6d-5ee8-468f-b1d5-cf33b95fda37 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T01:49:43Z |
| publishDate | 2016 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:99a80c6d-5ee8-468f-b1d5-cf33b95fda372022-03-27T00:15:54ZThe effect of diurnal variation, CYP2B6 genotype, and age on the pharmacokinetics of nevirapine in African ChildrenJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:99a80c6d-5ee8-468f-b1d5-cf33b95fda37Symplectic Elements at OxfordOxford University Press2016Bienczak, ACook, AWiesner, LMulenga, VKityo, CKekitiinwa, AWalker, AOwen, AGibb, DBurger, DMcIlleron, HDenti, P <h4>Objective</h4> <p>We aimed to characterise the effects of CYP2B6 polymorphisms, diurnal variation, and demographic factors on nevirapine pharmacokinetics in African children.</p> <h4>Methods</h4> <p>Nonlinear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration-time data from 414 children aged 0.3–15 years. </p> <h4>Results</h4> <p>Nevirapine pharmacokinetics was best described using a 1-compartmental disposition model with elimination through a well-stirred liver model accounting for first-pass effect and transit-compartment absorption. Intrinsic clearance was affected by diurnal variation (characterised using a cosine function with peak amplitude 29% at 12 noon) and CYP2B6 metaboliser status (extensive [EM] 516GG|983TT, reference; intermediate [IM] 516GT|983TT or 516GG|983TC, 17% lower; slow [SM] 516TT|983TT or 516GT|983TC, 50% lower; ultra-slow [USM] 516GG|983CC, 68% lower). Age was found to affect pre-hepatic bioavailability: 31.7% lower at birth and increasing exponentially. Median (90% CI) evening Cmin in the different metaboliser groups were 5.01 (3.01-7.47), 6.55 (3.65-13.32), 11.59 (5.44-22.71), and 12.32 (12.32-27.25) mg/L, respectively. Evening Cmin were <3mg/L in 43% of EM <6kg and 26% of IM <6kg, while 73% of SM and 88% USM in all weight-bands had evening Cmin >8 mg/L. Cmin was not markedly affected by administration time but by unequal splitting of the daily dose.</p> <h4>Conclusions</h4> <p>Diurnal variation does not greatly affect nevirapine exposure. However, when daily doses cannot be split equally, the larger dose should be given in the morning. To achieve homogeneous exposures, nevirapine doses for SM and USM should be reduced by 50%, and children <6kg with EM or IM metabolizer status should receive the same dose as children weighing 6-10 kg.</p> |
| spellingShingle | Bienczak, A Cook, A Wiesner, L Mulenga, V Kityo, C Kekitiinwa, A Walker, A Owen, A Gibb, D Burger, D McIlleron, H Denti, P The effect of diurnal variation, CYP2B6 genotype, and age on the pharmacokinetics of nevirapine in African Children |
| title | The effect of diurnal variation, CYP2B6 genotype, and age on the pharmacokinetics of nevirapine in African Children |
| title_full | The effect of diurnal variation, CYP2B6 genotype, and age on the pharmacokinetics of nevirapine in African Children |
| title_fullStr | The effect of diurnal variation, CYP2B6 genotype, and age on the pharmacokinetics of nevirapine in African Children |
| title_full_unstemmed | The effect of diurnal variation, CYP2B6 genotype, and age on the pharmacokinetics of nevirapine in African Children |
| title_short | The effect of diurnal variation, CYP2B6 genotype, and age on the pharmacokinetics of nevirapine in African Children |
| title_sort | effect of diurnal variation cyp2b6 genotype and age on the pharmacokinetics of nevirapine in african children |
| work_keys_str_mv | AT bienczaka theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT cooka theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT wiesnerl theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT mulengav theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT kityoc theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT kekitiinwaa theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT walkera theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT owena theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT gibbd theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT burgerd theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT mcilleronh theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT dentip theeffectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT bienczaka effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT cooka effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT wiesnerl effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT mulengav effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT kityoc effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT kekitiinwaa effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT walkera effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT owena effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT gibbd effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT burgerd effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT mcilleronh effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren AT dentip effectofdiurnalvariationcyp2b6genotypeandageonthepharmacokineticsofnevirapineinafricanchildren |