CYP3A5 genotype and its impact on vincristine pharmacokinetics and development of neuropathy in Kenyan children with cancer

Jodi L. Skiles, Chien Wei Chiang, Claire H. Li, Steve Martin, Ellen L. Smith, Gilbert Olbara, David R. Jones, Terry Vik, Saskia Mostert, Floor Abbink, Gertjan J. Kaspers, Lang Li, Festus Njuguna, Tammy J. Sajdyk, Jamie Renbarger

Research output: Contribution to journalArticle

Abstract

Background: Vincristine (VCR) is a critical part of treatment in pediatric malignancies and is associated with dose-dependent peripheral neuropathy (vincristine-induced peripheral neuropathy [VIPN]). Our previous findings show VCR metabolism is regulated by the CYP3A5 gene. Individuals who are low CYP3A5 expressers metabolize VCR slower and experience more severe VIPN as compared to high expressers. Preliminary observations suggest that Caucasians experience more severe VIPN as compared to nonCaucasians. Procedure: Kenyan children with cancer who were undergoing treatment including VCR were recruited for a prospective cohort study. Patients received IV VCR 2 mg/m2/dose with a maximum dose of 2.5 mg as part of standard treatment protocols. VCR pharmacokinetics (PK) sampling was collected via dried blood spot cards and genotyping was conducted for common functional variants in CYP3A5, multi-drug resistance 1 (MDR1), and microtubule-associated protein tau (MAPT). VIPN was assessed using five neuropathy tools. Results: The majority of subjects (91%) were CYP3A5 high-expresser genotype. CYP3A5 low-expresser genotype subjects had a significantly higher dose and body surface area normalized area under the curve than CYP3A5 high-expresser genotype subjects (0.28 ± 0.15 hr·m2/l vs. 0.15 ± 0.011 hr·m2/l, P = 0.027). Regardless of which assessment tool was utilized, minimal neuropathy was detected in this cohort. There was no difference in the presence or severity of neuropathy assessed between CYP3A5 high- and low-expresser genotype groups. Conclusion: Genetic factors are associated with VCR PK. Due to the minimal neuropathy observed in this cohort, there was no demonstrable association between genetic factors or VCR PK with development of VIPN. Further studies are needed to determine the role of genetic factors in optimizing dosing of VCR for maximal benefit.

Original languageEnglish (US)
Article numbere26854
JournalPediatric Blood and Cancer
Volume65
Issue number3
DOIs
StatePublished - Mar 1 2018

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Cytochrome P-450 CYP3A
Vincristine
Pharmacokinetics
Genotype
Peripheral Nervous System Diseases
Neoplasms
Microtubule-Associated Proteins
Body Surface Area
Multiple Drug Resistance
Clinical Protocols
Area Under Curve

Keywords

  • cancer
  • genotyping
  • neuropathy
  • pediatrics
  • vincristine

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Cite this

CYP3A5 genotype and its impact on vincristine pharmacokinetics and development of neuropathy in Kenyan children with cancer. / Skiles, Jodi L.; Chiang, Chien Wei; Li, Claire H.; Martin, Steve; Smith, Ellen L.; Olbara, Gilbert; Jones, David R.; Vik, Terry; Mostert, Saskia; Abbink, Floor; Kaspers, Gertjan J.; Li, Lang; Njuguna, Festus; Sajdyk, Tammy J.; Renbarger, Jamie.

In: Pediatric Blood and Cancer, Vol. 65, No. 3, e26854, 01.03.2018.

Research output: Contribution to journalArticle

Skiles, JL, Chiang, CW, Li, CH, Martin, S, Smith, EL, Olbara, G, Jones, DR, Vik, T, Mostert, S, Abbink, F, Kaspers, GJ, Li, L, Njuguna, F, Sajdyk, TJ & Renbarger, J 2018, 'CYP3A5 genotype and its impact on vincristine pharmacokinetics and development of neuropathy in Kenyan children with cancer', Pediatric Blood and Cancer, vol. 65, no. 3, e26854. https://doi.org/10.1002/pbc.26854
Skiles, Jodi L. ; Chiang, Chien Wei ; Li, Claire H. ; Martin, Steve ; Smith, Ellen L. ; Olbara, Gilbert ; Jones, David R. ; Vik, Terry ; Mostert, Saskia ; Abbink, Floor ; Kaspers, Gertjan J. ; Li, Lang ; Njuguna, Festus ; Sajdyk, Tammy J. ; Renbarger, Jamie. / CYP3A5 genotype and its impact on vincristine pharmacokinetics and development of neuropathy in Kenyan children with cancer. In: Pediatric Blood and Cancer. 2018 ; Vol. 65, No. 3.
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abstract = "Background: Vincristine (VCR) is a critical part of treatment in pediatric malignancies and is associated with dose-dependent peripheral neuropathy (vincristine-induced peripheral neuropathy [VIPN]). Our previous findings show VCR metabolism is regulated by the CYP3A5 gene. Individuals who are low CYP3A5 expressers metabolize VCR slower and experience more severe VIPN as compared to high expressers. Preliminary observations suggest that Caucasians experience more severe VIPN as compared to nonCaucasians. Procedure: Kenyan children with cancer who were undergoing treatment including VCR were recruited for a prospective cohort study. Patients received IV VCR 2 mg/m2/dose with a maximum dose of 2.5 mg as part of standard treatment protocols. VCR pharmacokinetics (PK) sampling was collected via dried blood spot cards and genotyping was conducted for common functional variants in CYP3A5, multi-drug resistance 1 (MDR1), and microtubule-associated protein tau (MAPT). VIPN was assessed using five neuropathy tools. Results: The majority of subjects (91{\%}) were CYP3A5 high-expresser genotype. CYP3A5 low-expresser genotype subjects had a significantly higher dose and body surface area normalized area under the curve than CYP3A5 high-expresser genotype subjects (0.28 ± 0.15 hr·m2/l vs. 0.15 ± 0.011 hr·m2/l, P = 0.027). Regardless of which assessment tool was utilized, minimal neuropathy was detected in this cohort. There was no difference in the presence or severity of neuropathy assessed between CYP3A5 high- and low-expresser genotype groups. Conclusion: Genetic factors are associated with VCR PK. Due to the minimal neuropathy observed in this cohort, there was no demonstrable association between genetic factors or VCR PK with development of VIPN. Further studies are needed to determine the role of genetic factors in optimizing dosing of VCR for maximal benefit.",
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T1 - CYP3A5 genotype and its impact on vincristine pharmacokinetics and development of neuropathy in Kenyan children with cancer

AU - Skiles, Jodi L.

AU - Chiang, Chien Wei

AU - Li, Claire H.

AU - Martin, Steve

AU - Smith, Ellen L.

AU - Olbara, Gilbert

AU - Jones, David R.

AU - Vik, Terry

AU - Mostert, Saskia

AU - Abbink, Floor

AU - Kaspers, Gertjan J.

AU - Li, Lang

AU - Njuguna, Festus

AU - Sajdyk, Tammy J.

AU - Renbarger, Jamie

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Background: Vincristine (VCR) is a critical part of treatment in pediatric malignancies and is associated with dose-dependent peripheral neuropathy (vincristine-induced peripheral neuropathy [VIPN]). Our previous findings show VCR metabolism is regulated by the CYP3A5 gene. Individuals who are low CYP3A5 expressers metabolize VCR slower and experience more severe VIPN as compared to high expressers. Preliminary observations suggest that Caucasians experience more severe VIPN as compared to nonCaucasians. Procedure: Kenyan children with cancer who were undergoing treatment including VCR were recruited for a prospective cohort study. Patients received IV VCR 2 mg/m2/dose with a maximum dose of 2.5 mg as part of standard treatment protocols. VCR pharmacokinetics (PK) sampling was collected via dried blood spot cards and genotyping was conducted for common functional variants in CYP3A5, multi-drug resistance 1 (MDR1), and microtubule-associated protein tau (MAPT). VIPN was assessed using five neuropathy tools. Results: The majority of subjects (91%) were CYP3A5 high-expresser genotype. CYP3A5 low-expresser genotype subjects had a significantly higher dose and body surface area normalized area under the curve than CYP3A5 high-expresser genotype subjects (0.28 ± 0.15 hr·m2/l vs. 0.15 ± 0.011 hr·m2/l, P = 0.027). Regardless of which assessment tool was utilized, minimal neuropathy was detected in this cohort. There was no difference in the presence or severity of neuropathy assessed between CYP3A5 high- and low-expresser genotype groups. Conclusion: Genetic factors are associated with VCR PK. Due to the minimal neuropathy observed in this cohort, there was no demonstrable association between genetic factors or VCR PK with development of VIPN. Further studies are needed to determine the role of genetic factors in optimizing dosing of VCR for maximal benefit.

AB - Background: Vincristine (VCR) is a critical part of treatment in pediatric malignancies and is associated with dose-dependent peripheral neuropathy (vincristine-induced peripheral neuropathy [VIPN]). Our previous findings show VCR metabolism is regulated by the CYP3A5 gene. Individuals who are low CYP3A5 expressers metabolize VCR slower and experience more severe VIPN as compared to high expressers. Preliminary observations suggest that Caucasians experience more severe VIPN as compared to nonCaucasians. Procedure: Kenyan children with cancer who were undergoing treatment including VCR were recruited for a prospective cohort study. Patients received IV VCR 2 mg/m2/dose with a maximum dose of 2.5 mg as part of standard treatment protocols. VCR pharmacokinetics (PK) sampling was collected via dried blood spot cards and genotyping was conducted for common functional variants in CYP3A5, multi-drug resistance 1 (MDR1), and microtubule-associated protein tau (MAPT). VIPN was assessed using five neuropathy tools. Results: The majority of subjects (91%) were CYP3A5 high-expresser genotype. CYP3A5 low-expresser genotype subjects had a significantly higher dose and body surface area normalized area under the curve than CYP3A5 high-expresser genotype subjects (0.28 ± 0.15 hr·m2/l vs. 0.15 ± 0.011 hr·m2/l, P = 0.027). Regardless of which assessment tool was utilized, minimal neuropathy was detected in this cohort. There was no difference in the presence or severity of neuropathy assessed between CYP3A5 high- and low-expresser genotype groups. Conclusion: Genetic factors are associated with VCR PK. Due to the minimal neuropathy observed in this cohort, there was no demonstrable association between genetic factors or VCR PK with development of VIPN. Further studies are needed to determine the role of genetic factors in optimizing dosing of VCR for maximal benefit.

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