Experience with Pharmacogenetics and Clinical Research in Africa - - PowerPoint PPT Presentation

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Experience with Pharmacogenetics and Clinical Research in Africa - - PowerPoint PPT Presentation

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Experience with Pharmacogenetics and Clinical Research in Africa Africas genomic diversity, an opportunity for advances in personalised healthcare Collen Masimirembwa (PhD, DPhil) Founder and Chief Scientific Officer African Institute of

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Experience with Pharmacogenetics and Clinical Research in Africa

Africa’s genomic diversity, an opportunity for advances in personalised healthcare

7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

Collen Masimirembwa (PhD, DPhil)

Founder and Chief Scientific Officer African Institute of Biomedical Science & Technology Zimbabwe Harare www.aibst.org

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7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

Pharmacogenetics- the impact of genetic variability on our response to medicines One treatment ( type of drug or dosage) fits all ‘ a dying medical practice’ Personalised medicine - towards safer and efficacious treatment of disease Patient genetic status – major determinant in individualising treatment

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7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

“A lot of the failures in the industry in Phase III weren’t because these molecules didn’t work but because they only work in a specific patient population.’’ More than 60% of drug development programs have some personalized component, such as a biomarker or diagnostic. Furthermore, a new medicine that is “safe, effective, and differentiated is not enough,” “You need to be all of those three things and have somebody pay for your medicine.”

Chemical & Engineering News , Issue Date: July 30, 2012. American Chemical Society

Industry on personalized Healthcare

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Pharmacogenetic/genomic implications

 Drug Discovery:

  • Target identification and validation on gene variants common in non-

African populations Risk for non-responder patient subgroups in Africa

 Drug Development:

  • Clinical studies conducted in non-African populations

Risk for wrong dose regimens and safety margins in African populations

 Pharmacogenomic diagnostic tests

  • Biomarkers for safety and efficacy established in non-African

populations Risk for lack of specificity or relevance in African populations

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Physical & Cultural Diversity Genetic Diversity

Genomic Diversity of African populations

The out-of-Africa Theory

African populations more genetically different compared to Caucasian or Asian populations (bottle-neck effect)  Studying genomics of African populations should give more insight into human variation

Linkage Disequilibrium (LD) (large common Haplotype blocks) (more variation in Haplotype blocks)

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Late but Promising Entry of Africa into Genomics Research

7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

2003 1st Draft of the complete Human genome

December, 2003 (Accra, Ghana) The African Society for Human Genetics (AFSHG) http://afshg.org/ August 2003 (Nairobi, Kenya) African Pharmacogenomics Consortium www.aibst.com

AiBST Initiative Diasporan Africans Initiative

2003 The African Pharmacogenomics Consortium (APC) formed

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AiBST – APC Biobanking Initiative

Comprehensive BioBank of African populations in terms of number of Countries (5), number of samples (2000) and number of ethnic(9) groups

Matimba et al., 2008

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African Population substructure studies Illumina Human Chips (610K SNPs)

  • B. Assemblage of African HapMap populations,

HapMap YRI, HapMap MKK and HapMap LWK and AiBST-APC Biobank ethnic groups, Zimbabwe San (ZWD), Zimbabwe Shona (ZWS), Kenya Kikuyu (KNK), Luo (KNL), Maasai (KNM), Kenya mixed groups (KNP), Nigeria Ibo (NGI), Yoruba (NGY), Hausa (NGH) and mixed ethnic groups from Tanzania (TZ) using the two Eigenvectors A. Assemblage of AiBST-APC Biobank populations (Zimbabwe, Tanzania, Nigeria, Kenya in relation to populations in the HapMap European (HapMap TIS, HapMap CEU), Mexican (HapMap MEX), Indian (HapMap GIH) and Asians (Chinese (HapMap CHB, HapMap CHD), Japanese (HapMap JPT), Kenya Luhya (HapMap LWK), Kenya Maasai (HapMap MKK) and Nigeria Yoruba (HapMap YRI) based on the two most informative principle components.

Maimbo, Mushiroda, Kamataki, Nakamura, Masimirembwa et al, submitted

Oriental populations Caucasian populations

Diversity of African populations

Confirms the heterogenuity reported by others (more diverse populations included in this study)

African Populations

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Drug & Therapeutic area Drug & Clinical Indication for some drugs Approved Clinical Diagnostic Tool for Biomarker Fluoxetine, Clozapine, Thioridazine, Fluoxetine & Olanzapine, (Psychiatry), Metoprolol(Cardiovascular), Cevimeline (Dermatological & Dental), codeine (Analgesics), tamoxifene (Oncology) Thioridazine –QT prolongation: torsades de points, Tamoxifene – loss of efficacy among PMs and with CYP2D6 inhibitors CYP2D6 polymorphism, diazepam, (Psychiatry), esomeprazole, (Gastroenterology), Nelfinavir(antiviral), Voriconazole (antifungal), Tamoxifene (Oncology) Voriconazole - hepatotoxicity CYP2C19 polymorphism Celecoxib (Analgesic), Warfarin (Hematology) Warfarin (risk for bleeding) CYP2C9, VKORC1 polymorphism Abacavir (antivirals) Hypersensitivity reactions HLA polymorphism Carbamazepine(Neurology) Severe immunoallergic cutaneous HLA polymorphism Thioguanine, Mercaptopurine (Oncology), Azathioprine (Rheumatology), Azathioprine & 6-MP - Neutropenia TMP polymorphism Irinotecan, Nilotinib (Oncology) Irinotecan – diarrhea, neutropenia UGT polymorphism

Pharmacogenomic Biomarkers in Food and Drug Administration (FDA) and European Medicines Agency (EMA) drug labels

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7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

Pharmacogenetics Guided dosing of Substrate drugs of polymorphic enzymes

Kirchheiner et al, 2005

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Pharmacogenetics of Drug Metabolising Enzymes in African populations

7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

Matimba et al., 2008 (n = 1500 samples from the AiBST-APC Biobank)

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Status of Drug Metabolism Polymorphisms in major world populations

 8 Genes investigated: CYP2B6, 2C9, 2C19, 2D6, NAT-2, FMO, GSTT, GSTM  25 SNPs associated with increased, reduced and deficient enzyme function  22 populations (14 -African, 4 - Caucasians, and 4- Oriental)

Matimba et.al, 2008 Caucasian populations African populations Oriental populations

Differential Clustering based on major drug metabolising enzymes is predictive

  • f potential differences in Drug Efficacy and Safety among these populations

African American

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Reduced CYP2D6 activity in African populations (e.g. substrate drug, Metoprolol)

Probit plots blue - Swedes black - Africans red - Chinese

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1 2 3 0.0 0.5 1.0 1.5

log MR probability density

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  • 1.1
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0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9 2.1 100 200

  • 1.3
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0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9 10 20 30 40 50 60 70 80

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0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9 2.1 2.3 2.5 50 100 150 200 250

Caucasians (n=1055) Swedes Asians (n=696) Han: 282 Mongolia: 128 Wei: 156 Zang: 135 Africans (n=362) Ethiopians: 180 Zimbabweans: 69 Nigerians: 113 Masimirembwa & Bertilsson, unpublished

Population Median MR Chinese 1.32 Swedes 0.56 African 1.14

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Samples: A B C MR: 0.4 1.5 10.5 Variant Nucleotide Amino acid Sample A Similar to Ref. Similar to Ref. Sample B C1111T (exon 2) Thr107Ile Sample C C1111T (exon 2) G1638C (exon 3) C2850T (exon 6) G4180C (exon 9) Thr107Ile Silent Arg206Cys Ser486Thr Variant Bufuralol Dextrometh. CYP2D6.1 Km Vmax Vmax/Km 9.65+0.3 8.64+2.1 0.89+0.2 1.30+0.2 2.21+0.5 1.77+0.6 CYP2D6.17 Km Vmax Vmax/Km 21.0+3.6*** 4.74+2.5 0.22+0.1** 7.16+1.7*** 1.68+0.7 0.27+0.2* Masimirembwa et al., 1996, Bapiro et al., 2003

CYP2D6*17

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7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

What are the right Doses for African Populations?

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Biomarkers for Adverse Drug Reactions (ADRs) in Patients on HAART

D4T/3TC/EFV D4T/3TC/EFV/RH(+ TB) D4T/3TC/EFV/RHEZ +RHE D4T/3TC/NVP AZT/3TC/EFV AZT/3TC/EFV-RHEZ AZT/3TC/NVP AZT/DDI/LPR,RIT TDF/3TC/EFV TDF/3TC/EFV/RHEZ TDF/3TC/NVP TDF/FTC/LPr,rit TDF/3TC/LPr,rit RH(+Streptomycin) RHEZ

Lipodystrophy Case 15 1 3 9 3 1 16 5 1 Control 21 4 38 23 5 3 10 1 8 3 1 2 10 43 Skin Hypersensitivity Case 11 2 11 7 3 2 5 1 3 1 1 1 9 Control 25 3 30 25 5 2 21 0 10 3 2 9 34 Peripheral Neuropathy Case 19 3 28 18 2 1 19 0 13 3 1 1 2 4 33 Control 17 2 13 14 6 3 7 1 6 10 CNS Case 18 1 24 4 5 2 7 0 10 1 1 2 18 Control 18 4 17 28 3 2 19 1 3 2 1 1 1 8 25

Patients from Wilkins & Chitungwiza Hospitals Nemaura et al., ongoing work

High incidences of ADRs (70%)

Treatment challenge has shifted from drug availability to safety in their use!

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CYP2B6 polymorphism in the use of efavirenz in HIV/AIDS treatment

CYP2B6G516T allele frequency: 20% in Caucasians AND 50% in Africans

Rodriguez et al., 2006 Matimba et al., 2008

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2012-09-07 Collen Masimirembwa. PhD, DPhil

  • Gene-Dose Effect
  • Females higher drug conc.
  • All above 1.0 ug/L
  • 50% > 4.0 ug/L

Nyakutira et al., 2007

Standard dose of 600 mg/day in Caucasians results in over dosing in > 50% Zimbabweans

Therapeutic Window (1-4 ug/ml)

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7 September 2012

n = 49 CYP2B6*1 = 49% CYP2B6*6 (G516T) = 41 % (Gln to His) CYP2B6*18 (T983C) = 10% (Ile toThr)

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Nemaura et al., 2012.

Multivariate evaluation of the effect of CYP2B6G516T, Genotype, Gender, Weight on Efavirenz plasma concentration ranges

T(1) = above 4ug/ml T(0) = within the 1-4 ug/ml range

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2012-09-07 Collen Masimirembwa. PhD, DPhil

Proposed dosing algorithm

  • f efavirenz in African

populations

Nemaura et al, , 2012

20% of patients are TT genotype Reduced side effects Reduced cost of treatment

1 in 5 patients would need a third of the current standard dose!

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CYP2B6G516T Genotyping Method Validation and Comparison

PCR -RFLP RT_PCR DNA sequencing

100% agreement in genotype results among the three methods Labs can choose method of choice depending on resources and expertise Item PCR-RFLP RT-PCR Sequencing Equipment 10,000.00 USD 50,000.00 USD 150,000.00 USD Cost/Sample 50.00 USD 100.00 USD 100.00 USD

Dhoro et al., submitted

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In 2011, AiBST was selected an ANDi Centre of Excellence in DMPK & Toxicology

 One of the 32 selected CoE from a competitive screening

  • f 117 institutes, universities & companies in Africa

 CoE to work in integrated networks to champion drug discovery in Africa

Rubbing Shoulders with Giants!

We seek collaborations towards strengthening our contribution to DDD in Africa

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Acknowledgements

7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

WCoP IPICS AstraZeneca Novartis

EDCTP RIKEN

AiBST scientists for their youthful energy in pursuance of biomedical research excellence