Call | Senior Fellowship (SF) |
Programme | EDCTP2 |
Start Date | 2018-04-01 |
End Date | 2023-03-31 |
Project Code | TMA2016SF1508 |
Status | Active |
Pharmacogenomics Research And Clinical Excellence in the Treatment of Infectious Diseases in African
Institution | Country |
---|---|
African Institute of Biomedical Science & Technology (AIBST) | Zimbabwe |
Wilkins Infectious Disease Hospital (Harare) |
Title | University | Start Date | End Date |
---|---|---|---|
Medical Biochemistry and Biophysics | Karolinska Institute, Sweden | 1995-01-02 | 1995-11-30 |
Type | Name | Title | University | Start Date | End Date |
---|---|---|---|---|---|
Phd | Nyarai Shoko | Ms | UCT | 2014 | 2017 |
PhD | Benjamin Ebeshi | Dr | AOU | 2011 | 2011 |
MPhil | Lovejoy Nleya | Mr | UZ | 2012 | 2016 |
PhD | Britta Kjellander | Dr | Gothenburg Univ | 2010 | 2010 |
MPhil | Winnie Muzorandi | Mrs | UZ | 2011 | 2015 |
PhD | Nicholas Mwaura | Mr | UCT | 2011 | 2014 |
262 |
187 |
205 |
154 |
119 |
171 |
129 |
126 |
128 |
129 |
Call | Senior Fellowship (SF) |
Programme | EDCTP1 |
Start Date | 2012-11-01 |
End Date | 2014-12-31 |
Project Code | TA.2011.40200.052 |
Status | Completed |
A prospective study to evaluate a pharmacogenetic-guided dosing algorithm based on patient CYP2B6 genotype compared to the empirical standard dose in the safe and efficacious use of efavirenz in HIV/AIDS patients in Zimbabwe
Primary Objectives: 1. To compare efavirenz exposure levels in patients in whom the initiation dose is based on a pharmacogenetic algorithm with those in patients given the standard dose 2. To compare HIV viral load suppression and CD4 counts in patients in whom efavirenz dose is based on a pharmacogenetic algorithm with those in patients given the standard dose 3. To compare the incidences and severity of efavirenz associated adverse drug reactions; liver function, skin hypersensitivity reactions and central nervous system (CNS) effects in patients in whom the efavirenz dose is based on a pharmacogenetic algorithm with those given the standard dose 4. To validate the CYP2D6 genotyping method for use in the clinical study
Institution | Country |
---|---|
African Institute of Biomedical Science and Technology (AiBST) | Zimbabwe |
Prospective randomised controlled trial
Wilkins Infectious Disease Hospital (Harare) |
Chitugwiza Hospital, Opportunistic Infections Unit (Chitugwiza) |
HIV/AIDS and TB cohort in Zimbabwe. We have conclusively shown that the CYP2B6*6 genotype is predictive of high concentrations of Project Porftolio Page 333 of 622 efavirenz and predisposition to CNS sides effects and require only 200 mg of the drug instead of the standard 600 mg a day. We have also shown that for the other patients heterozygous, that those carrying one defect CYP2B6 allele and those without a defect should only be given 400 mg of efavirenz a day. Our findings are supported by a recent major study, ENCORE, which demonstrated the non-inferiority of 400 mg to the 600 mg efavirenz dose. This therefore represents the climax of our study which medicines control regulatory authorities should now consider towards revising the use of this drug. We have now engaged the Medicines Control Authority of Zimbabwe (MCAZ) and the National AIDS Council (NAC). We have also been on radio stations explaining our results to the public, an outreach that has been well received and patients phoned in expressing their appreciation of having the reason for their ADRs explained based on our study. The work has also resulted in secondary of achievements such as: (1) Establishment of a Clinical Trial Research Group whose purpose is to critically discuss the design and execution of clinical studies in African settings. (2) Four publications (3) Initiation of a Clinical Trial Unit (CTC) at one of the major hospitals in Zimbabwe, Chitungwiza General Hospital, for the conduct of Phase I Clinical Studies. (4) The completion of PhD studies and successful defence of the thesis in December 2014, by Milcah Dhoro on Pharmacogenetics of Efavirenz
African Institute of Biomedical Science and Technology (AIBST)
Chief Scientific Officer
2018 | HUGO (Human Genome Organisation) International Africa Award for innovative research contribution in genomics in Africa – 5 000 USD. |
2017 | 1st Prize Innovation Award, Gauteng Accelator Program (GAP) South Africa – 500 000 Rands. |
2017 | Research Council of Zimbabwe Robert Gabriel Mugabe Outstanding Research Award (Awarded by the President of Zimbabwe through RCZ) – 15 000 USD |
2014 | Certificate of Excellence in recognition of pioneering work in the field of Forensic DNA Services in Zimbabwe (Awarded by the Vice-President of Zimbabwe) |
1996 | Certificate of Distinction in Biochemistry, President Robert Mugabe, Government of Zimbabwe (Awarded by the President of Zimbabwe) – 10 000 USD. |
Type | Name | Title | University | Start Date | End Date |
---|---|---|---|---|---|
MPhil | Lovejoy Nleya | Mr | University of Zimbabwe | 2012 | 2016 |
PhD | Nyarai Shoko | Miss | University of Cape Town | 2014 | 2014 |
Molecular Diagnostics | Vanessa Chasi | Miss | National University of Science & Technology | 2014 | 2015 |
Drug-Herb Interactions | Winnie Muzorandi | Miss | University of Zimbabwe | 2011 | 2015 |
PGx | Milcah Dhoro | Ms | UZ | 2011 | 2014 |
Molecualr Virology | Benjamin Chimkangara | Mr | UZ | 2012 | 2015 |
Medicinal Chem. | Nicholas Mwaura | Mr | UCT | 2011 | 2014 |
ADME/Med. Chem. | Roslyn Thelingwani | Miss | UCT | 2008 | 2012 |
PGx | Margaret Oluka | Miss | UoN | 2006 | 2012 |
ADME/Med. Chem. | Britta Kjellander | Miss | Gothenburg Univ | 2010 | 2010 |
PGx | Benjamin Ebeshi | Mr | OAU | 2011 | 2011 |
PGx | Alice Matimba | Miss | UCT | 2009 | 2009 |
HIV Drug Resistance | Justen Manasa | Mr | UZ | 2008 | 2008 |
PGx | Christopher Nyakutira | Mr | UZ | 2008 | 2008 |
Drug-Herb Interactions | Luther Gwaza | Mr | UZ | 2008 | 2008 |
PK | Simbarashe Zvada | Mr | UZ | 2011 | 2011 |
PGx | Emmanuel Chigutsa | Mr | UZ | 2010 | 2010 |
ADMET | Roslyn Thelingwani | Miss | UZ | 2007 | 2007 |
ADMET | Roslyn Thelingwani | Miss | UZ | 2005 | 2005 |
ADMET | AnnCharlotte Egnell | Ms | Gothenburg Univ. | 2002 | 2002 |
ADMET | Lovisa Afzelius | Ms | Gothenburg Univ. | 1999 | 1999 |
ADMET | Anna Åhgren | Ms | Gothenburg Univ. | 2001 | 2001 |
ADMET/PK | Tashinga Bapiro | Mr | UZ | 2004 | |
ADMET/Med Chem. | Lovisa Afzelius | Miss | Uppsala Univ | 2004 | 2004 |
ADMET | Rose Hayeshi | Miss | UZ | 2008 | 2008 |
Role | Committee/board | Start Date | End Date |
---|---|---|---|
Member and Secretary | IUPHAR (International Union of Pharmacology) Drug Metabolism and Transporters Section | 2014 | |
Member | IUPHAR (International Union of Pharmacology) Pharmacogenetics Section | 2014 | |
International Advisor | Malaysian Society for the Advancement of Pharmacogenomics (MSAP | 2005 | 2010 |
President | The African Society of Drug Metabolism and Development | 2009 | |
Member | Laboratory Committee of the Medicines Control Authority of Zimbabwe (MCAZ) | 2004 | 2014 |
Fellow and Dean of the College of Life Sciences | Zimbabwe Academy of Science (ZAS) | 2007 | 2016 |
Chairperson & Founding Member | African Pharmacogenomics Consortium | 2003 | |
AAS Governing Council Southern African Representative | The African Academy of Sciences Governing Council | 2017 | |
President | African Pharmacogenomics Consortium | 2018 |
Institution | Degree | Year |
---|---|---|
Uinversity of Zimbabwe, Zimbabwe | BSc (Hons) (Biochemistry), University of Zimbabwe | 1989-05-04 |
University of Zimbabwe, Zimbabwe | DPhil (Biochemistry), | 1994-02-04 |
Karolinska Institute, Sweden | PhD (Medical Biochemistry and Biophysics | 1995-02-05 |
, |
Human Immuno-deficiency Virus (HIV)
Amodiaquine (AQ) metabolism to N-desethylamodiaquine (DEAQ) is the principal route of disposition in humans. Using human liver microsomes and two sets of recombinant human cytochrome P450 isoforms (from lymphoblastoids and yeast) we performed studies to identify the CYP isoform(s) involved in the metabolism of AQ. CYP2C8 was the main hepatic isoform that cleared AQ and catalyzed the formation of DEAQ. The extrahepatic P450s, 1A1 and 1B1, also cleared AQ and catalyzed the formation of an unknown metabolite M2. TheKm and Vmaxvalues for AQ N-desethylation were 1.2 μM and 2.6 pmol/min/pmol of CYP2C8 for recombinant CYP2C8, and 2.4 μM and 1462 pmol/min/mg of protein for human liver microsomes (HLMs), respectively. Relative contribution of CYP2C8 in the formation of DEAQ was estimated at 100% using the relative activity factor method. Correlation analyses between AQ metabolism and the activities of eight hepatic P450s were made on 10 different HLM samples. Both the formation of DEAQ and the clearance of AQ showed excellent correlations (r2 = 0.98 and 0.95) with 6α-hydroxylation of paclitaxel, a marker substrate for CYP2C8. The inhibition of DEAQ formation by quercetin was competitive withKi values of 1.96 for CYP2C8 and 1.56 μM for HLMs. Docking of AQ into the active site homology models of the CYP2C isoforms showed favorable interactions with CYP2C8, which supported the likelihood of an N-desethylation reaction. These data show that CYP2C8 is the main hepatic isoform responsible for the metabolism of AQ. The specificity, high affinity, and high turnover make AQ desethylation an excellent marker reaction for CYP2C8 activity.