Non-compartmental and population pharmacokinetic analysis of dapsone in healthy NIGERIANS: A pilot study.

Dapsone is employed for both non-dermatological and dermatological indications but with non-existent population pharmacokinetics (popPK) data in Nigerians. This study was therefore designed to develop a popPK model in Nigerians. Non-compartmental analysis and nonlinear mixed effects modelling were utilized for data analysis. Eleven participants administered 50 mg dapsone tablet were included in the analysis. Derived pharmacokinetic parameters were: Cmax = 1.16 ± 0.32 µg/mL, Tmax = 3.77 ± 2.40 h, and t1/2z = 30.23 ± 11.76 h. PopPK model parameter estimates with inter-individual variability were Tlag = 0.40 h (10.0%, fixed); ka = 1.78 h-1 (75.9%); V/F = 89.25 L (21.6%); and Cl/F = 1.32 Lh-1 (27.7%). Sex was significantly associated with Cl/F, and body weight with V/F. Best popPK model was one-compartment with lag time, and first-order absorption and elimination. Sex and body weight significantly influenced the clearance and distribution volume of dapsone respectively.

Comparison of efavirenz levels in blood and hair with pharmacy refills as measures of adherence and predictors of viral suppression among people living with HIV in Nigeria.

BACKGROUND: Strategies to support adherence are constrained by the lack of tools to objectively monitor medication intake in low-resource settings. Pharmacologic measures are objective, but pharmacy refill data is more accessible and cost-efficient. This study compared short-term and long-term efavirenz (EFV) drug levels with pharmacy refill adherence data (PRA) and evaluated their ability to predict viral suppression among people living with HIV in Nigeria. METHODS: Paired hair and dried blood spot (DBS) samples were obtained from 91 adults living with HIV receiving 600 mg EFV-based antiretroviral therapy (ART) and EFV concentrations were measured via validated methods using liquid-chromatography-mass-spectrometry. PRA was estimated from pharmacy records, based on the number of days a patient collected medication before or after the scheduled pick-up date. PRA was categorized into ≤ 74%, 75-94% and ≥ 95%, defined as poor, medium and high adherence, respectively. HIV viral loads closest to the hair sampling time (within 6 months) were also abstracted. Receiver Operating Characteristics (ROC) curve analyses compared the ability of adherence metrics to predict viral suppression. RESULTS: Based on PRA, 81% of participants had high adherence while 11% and 8% had medium and poor adherence, respectively. The median (IQR) EFV concentrations were 6.85 ng/mg (4.56-10.93) for hair and 1495.6 ng/ml (1050.7-2365.8) for DBS. Of the three measures of adherence, hair EFV concentration had the highest Area Under Curve (AUC) to predict viral suppression. Correlations between EFV concentrations in DBS and hair with PRA were positive (r = 0.12, P = 0.27 and r = 0.21, P = 0.05, respectively) but not strong. CONCLUSIONS: EFV concentrations in hair were the strongest predictor of viral suppression and only weakly correlated with pharmacy refill adherence data in Nigeria. This study suggests that resource-limited settings may benefit from objective adherence metrics to monitor and support adherence.

Oncology Training Needs Assessment Among Health Care Professionals in Nigeria.

PURPOSE: This study investigated the status of training and preparedness for oncology practice and research and degree of interprofessional collaboration among health care professionals in the six geopolitical regions of Nigeria. METHODS: A convergent parallel mixed methods design was used. Three hundred seventeen respondents completed a three-part, online questionnaire. Self-rated competencies in oncology research (26 items), oncology practice (16 items), and interprofessional collaboration (nine items) were assessed with a one- to five-point Likert scale. Six key informant and 24 in-depth interviews were conducted. Descriptive statistics, analysis of variance, and pairwise t-test were used to analyze the quantitative data, whereas thematic analysis was used for the qualitative data. RESULTS: Respondents were mostly female (65.6%) with a mean age of 40.5 ± 8.3 years. Respondents include 178 nurses (56.2%), 93 medical doctors (29.3%), and 46 pharmacists (14.5%). Self-assessed competencies in oncology practice differed significantly across the three groups of health care professionals (F = 4.789, P = .009). However, there was no significant difference across professions for competency in oncology research (F = 1.256, P = .286) and interprofessional collaboration (F = 1.120, P = .327). The majority of respondents (267, 82.4%) felt that educational opportunities in oncology-associated research in the country are inadequate and that this has implications for practice. Key training gaps reported include poor preparedness in data analysis and bioinformatics (138, 43.5%), writing clinical trials (119, 37.5%), and writing grant/research proposals (105, 33.1%). Challenges contributing to gaps in cancer research include few trained oncology specialists, low funding for research, and inadequate interprofessional collaboration. CONCLUSION: This study highlights gaps in oncology training and practice and an urgent need for interventions to enhance interprofessional training to improve quality of cancer care in Nigeria. These would accelerate progress toward strengthening the health care system and reducing global disparities in cancer outcomes.

Quinoline Antimalarials Increase the Antibacterial Activity of Ampicillin.

Bacterial and malaria co-infections are common in malaria endemic countries and thus necessitate co-administration of antibiotics and antimalarials. There have long been anecdotal clinical reports of interactions between penicillins and antimalarial agents, but the nature and mechanisms of these interactions remain to be investigated. In this study, we employed antimicrobial interaction testing methods to study the effect of two antimalarials on the antibacterial activity of ampicillin in vitro. Paper strip diffusion, a modified disc diffusion and checkerboard methods were used to determine the nature of interactions between ampicillin and quinoline antimalarials, chloroquine and quinine, against Gram-positive and Gram-negative bacteria. The impact of antimalarials and ampicillin-antimalarial drug combinations on cell integrity of test bacteria were determined by measuring potassium release. The tested antimalarials did not show substantial antibacterial activity but quinine was bactericidal at high concentrations. Chloroquine and quinine increased ampicillin activity, with increasing concentrations extending the antibacterial's inhibition zones by 2.7-4.4 mm and from 1.1 to over 60 mm, respectively. Observed interactions were largely additive with Fractional Inhibitory Concentration Indices of >0.5-1 for all ampicillin-antimalarial combinations. Quinine and, to a lesser extent, chloroquine increase the activity of ampicillin and potentially other ß-lactams, which has implications for combined clinical use.

Implementing oncology clinical trials in Nigeria: a model for capacity building.

BACKGROUND: There is both higher mortality and morbidity from cancer in low and medium income countries (LMICs) compared with high income countries (HICs). Clinical trial activities and development of more effective and less toxic therapies have led to significant improvements in morbidity and mortality from cancer in HICs. Unfortunately, clinical trials remain low in LMICs due to poor infrastructure and paucity of experienced personnel to execute clinical trials. There is an urgent need to build local capacity for evidence-based treatment for cancer patients in LMICs. METHODS: We conducted a survey at facilities in four Teaching Hospitals in South West Nigeria using a checklist of information on various aspects of clinical trial activities. The gaps identified were addressed using resources sourced in partnership with investigators at HIC institutions. RESULTS: Deficits in infrastructure were in areas of patient care such as availability of oncology pharmacists, standard laboratories and diagnostic facilities, clinical equipment maintenance and regular calibrations, trained personnel for clinical trial activities, investigational products handling and disposals and lack of standard operating procedures for clinical activities. There were two GCP trained personnel, two study coordinators and one research pharmacist across the four sites. Interventions were instituted to address the observed deficits in all four sites which are now well positioned to undertake clinical trials in oncology. Training on all aspects of clinical trial was also provided. CONCLUSIONS: Partnerships with institutions in HICs can successfully identify, address, and improve deficits in infrastructure for clinical trial in LMICs. The HICs should lead in providing funds, mentorship, and training for LMIC institutions to improve and expand clinical trials in LMIC countries.

ARETTA: Assessing Response to Neoadjuvant Taxotere and Subcutaneous Trastuzumab in Nigerian Women With HER2-Positive Breast Cancer: A Study Protocol.

Human epidermal growth factor receptor 2 (HER2) subtype of breast cancer is aggressive, leading to a poor outcome. Targeted therapy with trastuzumab has been shown to be effective in the treatment of HER2-positive breast cancer. Cardiotoxicity is a specific adverse effect associated with trastuzumab. The initial formulation of trastuzumab was intravenous, but presently, a subcutaneous formulation (Herceptin SC) is available. Insufficient data on the response rate and cardiotoxic effects of trastuzumab among indigenous Black populations exist. In all studies evaluating the efficacy and toxicity of trastuzumab alone or in combination with chemotherapy, indigenous Black populations in Africa were not included, yet they are the ones most likely to benefit from highly effective cancer medicines. This is partly due to poor oncology clinical trial infrastructure in sub-Saharan Africa. The ARETTA study protocol (ClinicalTrials.gov identifier: NCT03879577) is a phase II multicenter feasibility study to evaluate the efficacy and toxicity of docetaxel given every 3 weeks for 4 cycles plus trastuzumab in 60 previously untreated women with nonmetastatic breast cancer. The primary endpoint is to assess the proportion of patients with complete pathologic response. Secondary endpoints include the number of patients who require dose delays in docetaxel and trastuzumab attributed to hematologic, GI, and cardiac toxicity. Pharmacokinetic profiles of subcutaneous trastuzumab will also be determined. The ARETTA study will provide important information on the clinical response and cardiac safety of subcutaneous trastuzumab in combination with docetaxel among indigenous African women with nonmetastatic breast cancer. It can also be used as a blueprint for conducting biomarker-driven oncology clinical trials in low-resource settings such as sub-Saharan Africa.

Causes and remedies for low research productivity among postgraduate scholars and early career researchers on non-communicable diseases in Nigeria.

OBJECTIVE: The aim of the descriptive, cross sectional, questionnaire-based study reported here was to explore the causes of low productivity in non-communicable diseases research among postgraduate scholars and early career researchers in Nigeria and identify measures that could facilitate increased research output. RESULTS: The 89 respondents were masters-level, doctoral scholars and resident doctors who attended a workshop. Majorities of the respondents (over 70%) either agreed or strongly agreed that factors contributing to poor non-communicable diseases research productivity include a dearth of in-country researchers with specialized skills, inability of Nigerian researchers to work in multidisciplinary teams, poor funding for health research, sub-optimal infrastructural facilities, and limited use of research findings by policy makers. Almost all the respondents (over 90%) agreed that potential strategies to facilitate non-communicable diseases research output would include increased funding for research, institutionalization of a sustainable, structured capacity building program for early career researchers, establishment of Regional Centers for Research Excellence, and increased use of research evidence to guide government policy actions and programs.

N-acetyltransferase 2 enzyme genotype-phenotype discordances in both HIV-negative and HIV-positive Nigerians.

BACKGROUND: The N-acetyltransferase 2 (NAT2) enzyme has been understudied in Nigerians including genotype-phenotype association studies. OBJECTIVE: The aim of this study was NAT2 haplotype identification and genotype-phenotype investigations in HIV-positive and HIV-negative Nigerians. PATIENTS AND METHODS: Phenotypes included self-reported sulphonamide hypersensitivity survey, experimental and computational NAT2 phenotyping. The NAT2 gene was amplified by PCR. Gene sequencing used ABI 3730 and Haploview 4.2 for haplotype reconstruction. Genotype-phenotype analyses used the χ P-value and odds ratio with a 95% confidence interval. RESULTS: Self-reported sulphonamide hypersensitivity showed a prevalence of 3.1 and 12.4% in HIV-positive and HIV-negative Nigerians, respectively. NAT2 genetic variants 191G>A, 282C>T, 341T>C, 481C>T, 590G>A, 803A>G and 857G>A were not significantly different between both groups (odds ratio=0.87; 95% confidence interval: 0.54-1.38, P=0.55). Nine haplotypes: NAT2*4, NAT2*12A, NAT2*13A, NAT2*5B, NAT2*6A, NAT2*7B, NAT2*5C, NAT2*14B and NAT2*14A had frequencies more than 1%, whereas NAT2*12B had 1.1% in the HIV-positive and 0.4% in the HIV-negative group. Overall, slow acetylator haplotypes made up 68%. The NAT2*12 signature single-nucleotide polymorphism was in high linkage disequilibrium with signature single-nucleotide polymorphism for NAT2*13 (D'=0.97, r=0.61) and NAT2*5 (D'=0.98, r=0.64). Genotype-phenotype association analysis showed haplotypes NAT2*13A, NAT2*5C, NAT2*7B and NAT2*14A to be associated strongly with the slow metabolic phenotype (P=0.002, 0.029, 0.032 and 0.050, respectively). Computational phenotypes were similar, with 30.9, 66 and 3.1% for slow, intermediate and rapid acetylators, respectively, among HIV-positive Nigerians and 31.2, 66.3 and 2.5% among the HIV-negative group. Overall, slow phenotypes made up 31%. CONCLUSION: NAT2 haplotype frequencies are similar in Nigerians, irrespective of HIV status, but genotype-phenotype discordances exist.