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

Experience with Pharmacogenetics and Clinical Research in Africa Africa’s genomic diversity, an opportunity for advances in personalised healthcare Collen Masimirembwa (PhD, DPhil) Founder and Chief Scientific Officer African Institute of Biomedical Science & Technology Zimbabwe Harare www.aibst.org 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 7 September 2012 Collen Masimirembwa. DPhil, Ph.D. Patient genetic status – major determinant in individualising treatment

Industry on personalized Healthcare “ 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 7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

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

Genomic Diversity of African populations The out-of-Africa Theory Genetic Diversity Physical & Cultural Diversity (large common Haplotype blocks) (more variation in Haplotype blocks) Linkage Disequilibrium (LD)  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

Late but Promising Entry of Africa into Genomics Research 2003 1 st Draft of the complete Human genome AiBST Initiative Diasporan Africans Initiative December, 2003 (Accra, Ghana) August 2003 (Nairobi, Kenya) The African Society for African Pharmacogenomics Consortium Human Genetics (AFSHG) www.aibst.com http://afshg.org/ 2003 The African Pharmacogenomics Consortium (APC) formed 7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

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

African Population substructure studies Illumina Human Chips (610K SNPs) African Caucasian Populations populations Diversity of African populations Oriental populations Confirms the heterogenuity reported by others ( more diverse populations included in this study ) A. Assemblage of AiBST-APC Biobank populations B . Assemblage of African HapMap populations, (Zimbabwe, Tanzania, Nigeria, Kenya in relation HapMap YRI, HapMap MKK and HapMap to populations in the HapMap European (HapMap LWK and AiBST-APC Biobank ethnic groups, TIS, HapMap CEU), Mexican (HapMap MEX), Zimbabwe San (ZWD), Zimbabwe Shona (ZWS), Indian (HapMap GIH) and Asians (Chinese (HapMap Kenya Kikuyu (KNK), Luo (KNL), Maasai (KNM), CHB, HapMap CHD), Japanese (HapMap JPT), Kenya mixed groups (KNP), Nigeria Ibo (NGI), Kenya Luhya (HapMap LWK), Kenya Maasai (HapMap Yoruba (NGY), Hausa (NGH) and mixed ethnic MKK) and Nigeria Yoruba (HapMap YRI) based on groups from Tanzania (TZ) using the the two most informative principle components. two Eigenvectors Maimbo, Mushiroda, Kamataki, Nakamura, Masimirembwa et al, submitted

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

Pharmacogenetics Guided dosing of Substrate drugs of polymorphic enzymes 7 September 2012 Collen Masimirembwa. DPhil, Ph.D. Kirchheiner et al, 2005

Pharmacogenetics of Drug Metabolising Enzymes in African populations (n = 1500 samples from the AiBST-APC Biobank) Matimba et al., 2008 7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

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) Caucasian populations African American Oriental African populations populations Differential Clustering based on major drug metabolising enzymes is predictive of potential differences in Drug Efficacy and Safety among these populations Matimba et.al, 2008

Reduced CYP2D6 activity in African populations (e.g. substrate drug, Metoprolol) Probit plots blue - Swedes 250 Caucasians (n=1055) black - Africans 200 Swedes red - Chinese� 1.5 150 probability density 100 1.0 50 0 0.5 -1.7 -1.5 -1.3 -1.1 -0.9 -0.7 -0.5 -0.3 -0.1 0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9 2.1 2.3 2.5 200 Asians (n=696) 0.0 -3 -2 -1 0 1 2 3 Han: 282 log MR Mongolia: 128 Population Median MR 100 Wei: 156 1.32 Chinese Zang: 135 Swedes 0.56 0 -1.5 -1.3 -1.1 -0.9 -0.7 -0.5 -0.3 -0.1 0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9 2.1 1.14 African 80 Africans (n=362) 70 Ethiopians: 180 60 Zimbabweans: 69 50 40 Nigerians: 113 30 20 10 0 -1.3 -1.1 -0.9 -0.7 -0.5 -0.3 -0.1 0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5 1.7 1.9 Masimirembwa & Bertilsson, unpublished

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

What are the right Doses for African Populations? 7 September 2012 Collen Masimirembwa. DPhil, Ph.D.

Biomarkers for Adverse Drug Reactions (ADRs) in Patients on HAART AZT/3TC/EFV-RHEZ TDF/3TC/EFV/RHEZ RH(+Streptomycin) D4T/3TC/EFV/RHEZ D4T/3TC/EFV/RH(+ AZT/DDI/LPR,RIT TDF/3TC/LPr,rit TDF/FTC/LPr,rit D4T/3TC/NVP TDF/3TC/NVP Patients from AZT/3TC/NVP D4T/3TC/EFV AZT/3TC/EFV TDF/3TC/EFV Wilkins & +RHE RHEZ TB) Chitungwiza Hospitals Case 15 1 3 9 3 1 16 0 5 0 1 0 0 0 0 Lipodystrophy Control 21 4 38 23 5 3 10 1 8 3 0 1 2 10 43 Case 11 2 11 7 3 2 5 1 3 0 1 1 0 1 9 Skin Hypersensitivity Control 25 3 30 25 5 2 21 0 10 3 0 0 2 9 34 19 3 28 18 2 1 19 0 13 3 1 1 2 4 33 Peripheral Case Neuropathy Control 17 2 13 14 6 3 7 1 0 0 0 0 0 6 10 Case 18 1 24 4 5 2 7 0 10 1 0 0 1 2 18 CNS Control 18 4 17 28 3 2 19 1 3 2 1 1 1 8 25 High incidences of ADRs (70%) Treatment challenge has shifted from drug availability to safety in their use! Nemaura et al., ongoing work

CYP2B6 polymorphism in the use of efavirenz in HIV/AIDS treatment Rodriguez et al., 2006 CYP2B6G516T allele frequency: 20% in Caucasians AND 50% in Africans Matimba et al ., 2008

• Gene-Dose Effect • Females higher drug conc. • All above 1.0 ug/L • 50% > 4.0 ug/L Therapeutic Window (1-4 ug/ml) Nyakutira et al., 2007 Standard dose of 600 mg/day in Caucasians results in over dosing in > 50% Zimbabweans 2012-09-07 Collen Masimirembwa. PhD, DPhil

n = 49 CYP2B6*1 = 49% CYP2B6*6 (G516T) = 41 % (Gln to His) CYP2B6*18 (T983C) = 10% (Ile toThr) 7 September 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 Nemaura et al., 2012.