Role of pharmacogenetics in rifampicin pharmacokinetics and the potential effect on TB–rifampicin sensitivity among Ugandan patients

BACKGROUND: Suboptimal anti-TB drugs exposure may cause multidrug-resistant TB. The role of African predominant SLCO1B1 variant alleles on rifampicin pharmacokinetics and the subsequent effect on the occurrence of Mycobacterium tuberculosis-rifampicin sensitivity needs to be defined. We describe the rifampicin population pharmacokinetics profile and investigate the relevance of SLCO1B1 genotypes to rifampicin pharmacokinetics and rifampicin-TB sensitivity status. METHODS: Fifty patients with TB (n=25 with rifampicin-resistant TB and n=25 with rifampicin-susceptible TB) were genotyped for SLOC1B1 rs4149032 (g.38664C>T), SLOC1B1*1B (c.388A>G) and SLOC1B1*5 (c.521 T>C). Steady state plasma rifampicin levels were determined among patients infected with rifampicin-sensitive TB. Data were analysed using NONMEM to estimate population rifampicin pharmacokinetics as well as the effect of SLOC1B1 genotypes on rifampicin pharmacokinetics and on rifampicin-TB sensitivity status. RESULTS: Overall allele frequencies of SLOC1B1 rs4149032, *1B and *5 were 0.66, 0.90 and 0.01, respectively. Median (IQR) Cmax and Tmax were 10.2 (8.1-12.5) mg/L and 1.7 (1.125-2.218) h, respectively. Twenty-four percent of patients exhibited Cmax below the recommended 8-24 mg/L range. SLOC1B1 genotypes, gender and age did not influence rifampicin pharmacokinetics or TB-rifampicin sensitivity. CONCLUSIONS: Although SLOC1B1 genotype, age and gender do not influence either rifampicin pharmacokinetics or rifampicin-TB sensitivity status, one in every four Ugandan TB patients achieve subtherapeutic plasma rifampicin concentrations

Poor immunological recovery among severely immunosuppressed antiretroviral therapy-naïve Ugandans

Sarah Nanzigu,1,2 Ronald Kiguba,1 Joseph Kabanda,3 Jackson K Mukonzo,1 Paul Waako,1 Cissy Kityo,4 Fred Makumbi31Department of Pharmacology and Therapeutics, Makerere University College of Health Sciences, Kampala, Uganda; 2Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden; 3Institute of Public Health, Makerere University College of Health Sciences, Kampala, Uganda; 4Joint Clinic Research Centre, Kampala, UgandaIntroduction: CD4 T lymphocytes remain the surrogate measure for monitoring HIV progress in resource-limited settings. The absolute CD4 cell counts form the basis for antiretroviral therapy (ART) initiation and monitoring among HIV-infected adults. However, the rate of CD4 cell change differs among patients, and the factors responsible are inadequately documented.Objective: This study investigated the relationship between HIV severity and ART outcomes among ART-na&iuml;ve Ugandans, with the primary outcome of complete immunological recovery among patients of different baseline CD4 counts.Methods: Patients&#39; records at two HIV/ART sites &ndash; the Joint Clinic Research Centre (JCRC) in the Kampala region and Mbarara Hospital in Western Uganda &ndash; were reviewed. Records of 426 patients &ndash; 68.3% female and 63.2% from JCRC &ndash; who initiated ART between 2002 and 2007 were included. HIV severity was based on baseline CD4 cell counts, with low counts considered as severe immunosuppression, while attaining 418 CD4 cells/&micro;L signified complete immunological recovery. Incidence rates of complete immunological recovery were calculated for, and compared between baseline CD4 cell categories: <50 with &ge;50, <100 with &ge;100, <200 with &ge;200, and &ge;200 with &ge;250 cells/&micro;L.Results: The incidence of complete immunological recovery was 158 during 791.9 person-years of observation, and patients with baseline CD4 &ge; 200 cells/&micro;L reached the end point of immunological recovery 1.89 times faster than the patients with baseline CD4 < 200 cells/&micro;L. CD4 cell change also differed by time, sex, and site, with a faster increase observed during the first year of treatment. CD4 cell increase was faster among females, and among patients from Mbarara.Conclusion: Initiating ART at an advanced HIV stage was the main reason for poor immunological recovery among Ugandans. Earlier ART initiation might lead to better immunological responses.Keywords: baseline CD4 cells, HIV severity, immunological recovery, ART outcome, AR

Pharmacokinetics of the nonnucleoside reverse transcriptase inhibitor efavirenz among HIV-infected Ugandans.

BACKGROUND: Pharmacokinetic variability of the nonnucleoside reverse transcriptase inhibitor efavirenz has been documented, and high variation in trough concentrations or clearance has been found to be a risk for virological failure. Africans population exhibits greater variability in efavirenz concentrations than other ethnic groups, and so a better understanding of the pharmacokinetics of the drug is needed in this population. This study characterized efavirenz pharmacokinetics in HIV-infected Ugandans. METHODS: Efavirenz plasma concentrations were obtained for 66 HIV-infected Ugandans initiating efavirenz- based regimens, with blood samples collected at eight time-points over 24 h on day 1 of treatment, and at a further eight time-points on day 14. Noncompartmental analysis was used to describe the pharmacokinetics of efavirenz. RESULTS: The mean steady-state minimum plasma concentration (C(min) ) of efavirenz was 2.9 µg/mL, the mean area under the curve (AUC) was 278.5 h µg/mL, and mean efavirenz clearance was 7.4 L/h. Although overall mean clearance did not change over the 2 weeks, 41.9% of participants showed an average 95.8% increase in clearance. On day 14, the maximum concentration (C(max) ) of efavirenz was >4 µg/mL in 96.6% of participants, while C(min) was 4 µg/mL, although only half maintained a high concentration until at least 8 h after dosing. CONCLUSION: The findings of this study show that HIV-infected patients on efavirenz may exhibit autoinduction to various extents, and this needs to be taken into consideration in the clinical management of individual patients. Efavirenz CNS toxicity during the initial phase of treatment may be related to C(max) , regardless of the sampling time

Pharmacogenetic-based efavirenz dose modification: suggestions for an African population and the different CYP2B6 genotypes.

Pharmacogenetics contributes to inter-individual variability in pharmacokinetics (PK) of efavirenz (EFV), leading to variations in both efficacy and toxicity. The purpose of this study was to assess the effect of genetic factors on EFV pharmacokinetics, treatment outcomes and genotype based EFV dose recommendations for adult HIV-1 infected Ugandans.In total, 556 steady-state plasma EFV concentrations from 99 HIV infected patients (64 female) treated with EFV/lamivudine/zidovidine were analyzed. Patient genotypes for CYP2B6 (*6 & *11), CYP3A5 (*3,*6 & *7) and ABCB1 c.4046A>G, baseline biochemistries and CD4 and viral load change from baseline were determined. A one-compartment population PK model with first-order absorption (NONMEM) was used to estimate genotype effects on EFV pharmacokinetics. PK simulations were performed based upon population genotype frequencies. Predicted AUCs were compared between the product label and simulations for doses of 300 mg, 450 mg, and 600 mg.EFV apparent clearance (CL/F) was 2.2 and 1.74 fold higher in CYP2B6*6 (*1/*1) and CYP2B6*6 (*1/*6) compared CYP2B6*6 (*6/*6) carriers, while a 22% increase in F1 was observed for carriers of ABCB1 c.4046A>G variant allele. Higher mean AUC was attained in CYP2B6 *6/*6 genotypes compared to CYP2B6 *1/*1 (p<0.0001). Simulation based AUCs for 600 mg doses were 1.25 and 2.10 times the product label mean AUC for the Ugandan population in general and CYP2B6*6/*6 genotypes respectively. Simulated exposures for EFV daily doses of 300 mg and 450 mg are comparable to the product label. Viral load fell precipitously on treatment, with only six patients having HIV RNA >40 copies/mL after 84 days of treatment. No trend with exposure was noted for these six patients.Results of this study suggest that daily doses of 450 mg and 300 mg might meet the EFV treatment needs of HIV-1 infected Ugandans in general and individuals homozygous for CYP2B6*6 mutation, respectively

Final model pharmacokinetic parameters.

<p>Ka = Mean population absorption rate constant, V = Mean population Volume of distribution, CL = Mean population clearance, F1 = Bioavailability fraction, IIV CL = inter-individual variability on Clearance in the population, RV = residual variability.</p

The individually weighted residuals (WRES) are plotted <i>vs.</i> time.

<p>The dashed line is the zero reference line while the solid line is a smooth nonparametric regression line. The plot demonstrates a good fit of all time point concentration data by the model.</p

Distribution of estimated patient AUC values by CYP2B6 genotype.

<p>CYP2B6*1/*1, CYP2B6 *1/*6, and CYP2B6 *6/*6. Dotted line = the mean AUC value in the product label.</p

Area under the curve (AUC) NONMEM estimate values for ABCB1 c. 4046A>G and or CYP2B6* 6 genotypes.

<p>The estimations are based on the predicted individual apparent clearance and bioavailability values.</p><p>mut = heterozygous plus homozygous variant, wt = homozygous variants.</p><p>Four patients did not have a reported ABCB1 genotype and one patient was ABCB1 G/G. These five subjects are not included in these summary statistics for ABCB1, but are included in the general CYP2B6*6 summary above.</p

HIV viral loads at baseline and day 84 of treatment and AUC of study participants who failed to attain viral suppression to below detection by day 84.

<p>Data are arranged in order of increasing AUC.</p