Background: In sub-Saharan Africa, the disease burden of malaria and HIV infections overlap. In settings with moderate-to-high malaria transmission intensity, pregnant women living with HIV (PWLHIV) require both antiretroviral therapy and malaria intermittent preventive treatment (IPTp). Dihydroartemisinin-piperaquine has been identified as a promising alternative to sulfadoxine-pyrimethamine for malaria prevention in pregnancy. However, another antimalarial drug, artesunate-amodiaquine, similar to dihydroartemisininpiperaquine, was previously shown to reduce dolutegravir exposure in non-pregnant adults. Objective: To investigate the effect of dihydroartemisinin-piperaquine for IPTp on dolutegravir plasma exposure in pregnant women on dolutegravir-based antiretroviral therapy. Methods: We conducted an open-label, non-randomised, fixed sequence, pharmacokinetic study in PWLHIV in Malawi. Dolutegravir concentrations were measured over a 24-hour period, before and after the recommended three-day treatment dose of dihydroartemisininpiperaquine in 12 pregnant women in their 2nd or 3rd trimester. Non-compartmental analysis was performed, and geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were generated to compare dolutegravir pharmacokinetic parameters between the two treatment periods. Results: Co-administration of dihydroartemisinin-piperaquine and dolutegravir increased dolutegravir's overall exposure (AUC0-24hr) and maximum concentration (Cmax) by 30% (GMR,1.30; 90% CI, 1.11-1.52) and 31% (GMR, 1.31; 90% CI,1.13-1.51), respectively. Furthermore, dolutegravir's trough (C24) concentration increased by 42% (GMR,1.42; 90% CI,1.09-1.85). The combined treatments were well tolerated with no serious adverse events observed. Conclusion: Dihydroartemisinin-piperaquine may be administered as IPTp with dolutegravir-based antiretroviral therapy in pregnant women as the modest increase in dolutegravir exposure, similar to pharmacokinetic parameter values published previously, assures its efficacy without any clinically significant adverse events observed in this small study

Background The World Health Organization (WHO) recommends dolutegravir in combination with a nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone as the preferred first-line regimen for people living with HIV (PLWHIV) initiating antiretroviral therapy (ART). Tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are both prodrugs of tenofovir. However, plasma tenofovir exposure is higher when given as TDF, and TAF yields lower plasma but higher intracellular tenofovir concentrations. Although generally well tolerated, excessive weight gain has been associated with dolutegravir and (TAF) in PLWHIV initiating ART or those switching from efavirenz- or TDF-containing ART. Interindividual variability in dolutegravir and tenofovir pharmacokinetics or the interindividual differences in host response may, in part, be explained by host genetics. We characterized associations between genetic polymorphisms and dolutegravir exposure, tenofovir clearance and magnitude of weight gain in Southern Africans initiating ART. Methods We collected clinical and laboratory data in adults randomized to initiate TAF or TDF in dolutegravir-containing arms of the ADVANCE trial (NCT03122262). We measured dolutegravir and tenofovir concentrations and developed population pharmacokinetic models for dolutegravir and tenofovir using non-linear mixed-effects modelling. Genome-wide genotyping followed by imputation was performed. Linear regression models examined associations between genetic polymorphisms and unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR), unexplained variability in tenofovir clearance, and percentage weight gain from baseline to week 48. Results Considering genetic associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR), the lowest P-value with AUCVAR was UGT1A1 rs887829 (P = 1.8 x 10-4 ), which was also associated with log10 bilirubin (P = 8.6 x 10-13). After adjusting for rs887829, AUCVAR was independently associated with rs28899168 in the UGT1A locus (P = 0.02), as were bilirubin concentrations (P = 7.7 x 10-8 ). In the population pharmacokinetic model, compared to C/C, rs887829 T/T and C/T were associated with 25.9% and 10.8% decreases in dolutegravir clearance, respectively. There were no significant genome-wide associations. Considering genetic associations with unexplained variability in tenofovir clearance, we found no significant associations with tenofovir clearance for either TAF or TDF among 5 polymorphisms previously associated with tenofovir pharmacokinetics (lowest P-value > 0.3 for each drug). Among 11 polymorphisms selected based on both prior strong association with any drug phenotype in PharmGKB and any genome-wide association with any trait in the GWAS catalog, IFNL4 rs12979860 T>C was significantly associated with increased tenofovir clearance (TAF: P = 0.003; TDF: P = 0.003). In genome-wide analyses, the lowest P-values for tenofovir clearance in the TAF and TDF arms were with LINC01684 rs9305223 (P = 3.0 x 10-8 ) and intergenic rs142693425 (P = 1.4 x 10-8 ), respectively. Four additional polymorphisms were genome-wide significant. In genome-wide multivariate linear regression analyses adjusting for baseline age, sex, concomitant NRTI, and population stratification, there were no significant associations between 59 polymorphisms relevant to dolutegravir and tenofovir disposition and the percentage weight gain. We found a genome-wide significant association between TMEM163 rs7590091 and percentage weight gain from baseline to week 48 (P = 3.7 x 10-8 ). Conclusion Among Southern African people living with HIV randomized to TAF or TDF, we identified several potential genetic associations with dolutegravir exposure, tenofovir clearance and weight gain. The novel associations between dolutegravir AUCVAR and rs28899168, tenofovir clearance and IFNL4 rs12979860, and weight gain and TMEM163 rs7590091 require independent replication. These findings enhance our understanding of dolutegravir and tenofovir pharmacogenetics among Southern Africans living with HIV.

Africa houses more than 50% of the 37 million people estimated to be living with HIV (PLWH). Although great strides have been made in increasing access to antiretroviral therapy, the number of new HIV infections remains high. In sub-Saharan Africa, co-infections of HIV, tuberculosis, and malaria are common because the three pandemics overlap considerably. Treatment of these co-infections is often challenging because of the potential for drug-drug interactions. Dolutegravir-based regimens are now the preferred first-line option for the management of HIV. Therefore, many African countries have transitioned most PLWH from efavirenz- to dolutegravir-based regimens. A fixed-dose combination containing dolutegravir, tenofovir, and lamivudine taken daily constitutes one of the most widely used regimens in Africa. In this thesis, we employ population pharmacokinetic modelling to optimise HIV treatment using data from healthy volunteers or PLWH, some of whom also have tuberculosis. We characterise dolutegravir pharmacokinetics, pharmacogenetics, and its drug-drug interaction with the antituberculosis drugs rifampicin and rifabutin and with the antimalarial drugs artemether-lumefantrine and artesunate-amodiaquine. We also describe the pharmacokinetics of tenofovir when dosed as either tenofovir disoproxil fumarate or tenofovir alafenamide in South Africans living with HIV. We found that rifampicin increases dolutegravir clearance more than twofold, leading to a reduction in its exposure. We confirmed that this interaction can be overcome with twice-daily dosing of 50-mg dolutegravir. We also demonstrate that a simpler regimen of 100 mg once daily may be sufficient. We also found that rifabutin decreases dolutegravir volume of distribution, but without an overall change in exposure. The interaction between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine was not clinically significant, and no dose adjustment is required when these are co-administered. Lastly, we demonstrate that polymorphisms within the UGT1A locus affect dolutegravir exposure among Africans. For tenofovir, we created a joint model that describes its disposition when given either as tenofovir disoproxil fumarate or tenofovir alafenamide. In conclusion, by employing pharmacometric techniques, we were able to analyze and pool data from different studies, including sparsely sampled data, and run simulations to test and inform alternative dosing scenarios.

Efavirenz, lopinavir, and ritonavir are antiretroviral drugs used for the treatment of HIV in South Africa. Plasma concentrations of these drugs are routinely monitored to ensure efficacy, minimise adverse effects, and adjust dosing. However, variability exists in patient treatment response and tolerability, which cannot always be explained by the therapeutic drug monitoring results. This may be due to variability in the amount of drug reaching the target site within the HIV-infected cells. Therefore, intracellular drug concentrations could provide a more accurate depiction of drug exposure. An alternative to intracellular drug concentrations could be the quantitation of drug not bound to plasma proteins as this is the portion able to diffuse into tissues and cells to exert a therapeutic effect. A method is described for the quantification of intracellular efavirenz, lopinavir, and ritonavir from one million human peripheral blood mononuclear cells. In addition, the quantification of unbound efavirenz, lopinavir, and ritonavir from human plasma using ultracentrifugation is demonstrated, including a novel surrogate matrix. The two methods were validated according to the United States Food and Drug Administration and European Medicines Agency guidelines and proven to be accurate, precise, and reproducible. Both methods were submitted to the United States National Institute of Allergy and Infectious Diseases' Clinical Pharmacology Quality Assurance group for review and have been approved for use on clinical samples. A proof-of-concept correlation study of intracellular, unbound, and total drug concentrations is described using blood samples from six HIV-positive patients. A further patient unresponsive to lopinavir treatment, despite total plasma concentrations within the normal therapeutic range, was also evaluated. Paired plasma and cell samples indicated that the drug reached the target site within the cells, eliminating a possible cause of treatment failure. These findings show the utility and validity of these methods in a clinical setting to provide an overall view of treatment response and support their novel application in individualised patient care in South Africa.

Indiana University-Purdue University Indianapolis (IUPUI) / The purpose of this study is to determine if propoxyphene and norpropoxyphene are mechanism-based (irreversible) inhibitors of CYP3A, and to determine if propoxyphene and norpropoxyphene are reversible inhibitors of CYP3A. Mechanismbased inhibition is a type of irreversible inhibition that results from an inhibitor or its metabolite binding to an enzyme during drug metabolism, which renders the enzyme nonfunctional. Propoxyphene is an analgesic that is frequently prescribed in the United States and Europe. It is metabolized by CYP3A enzymes, and is an irreversible inhibitor of CYP3A4. The major metabolite of propoxyphene is norpropoxyphene, which has not been extensively studied for enzyme inhibition. Proadifen (SKF-525a) is not a marketed drug, but it is a known CYP inhibitor that is structurally similar to propoxyphene and norpropoxyphene. Propoxyphene, norpropoxyphene, and proadifen were characterized in these studies with CYP3A4(+b5), CYP3A5(+b5) and pooled human liver microsomes. Time-dependent and concentration-dependent loss of activity of CYP3A was measured by formation of testosterone product. Propoxyphene and norpropoxyphene exhibited the greatest inhibition with CYP3A in human liver microsomes, followed by CYP3A4(+b5), and CYP3A5(+b5). Both compounds formed metabolic-inhibitor complexes with vi CYP3A4(+b5) and CYP3A5(+b5), but not with human liver microsomes. Proadifen was a more potent inhibitor of CYP3A4(+b5) than of human liver microsomes and CYP3A5(+b5). The KI values of propoxyphene and CYP3A4(+b5) and human liver microsomes fall within the range of reported therapeutic blood levels of propoxyphene, with reversible inhibition constants (Ki values) above therapeutic blood concentrations for propoxyphene and norpropoxyphene. The KI values of norpropoxyphene and CYP3A4(+b5) and human liver microsomes are higher than most reported blood levels, except for blood levels after repeated dosing of propoxyphene at high concentrations. The predicted change in the area under the plasma concentration versus time curve of an orally administered CYP3A substrate with propoxyphene (AUC'po/AUCpo) was calculated for common CYP3A substrates. The AUC'po/AUCpo ratios are four to twenty-five times higher with co-administration of propoxyphene based on in vitro kinetic parameters. Propoxyphene and norpropoxyphene may cause adverse events when chronically administered at high doses and/or when co-administered with other CYP3A substrates.

No description available.

Thesis (Ph. D.)--Rutgers University, 2009. / "Graduate Program in Management." Includes bibliographical references (p. 99-105).

No description available.

No description available.

Acyclovir is a synthetic purine nucleoside analogue with in vitro and in vivo inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). The efficacy of oral acyclovir is limited as a result of its low bioavailability (15-30%) as it is poorly water soluble and therefore requires a frequent dosing regimen. When orally administered, peak plasma concentration occurs after 1.5–2.5 hours, while its elimination half-life is approximately 2-3 hours. Acyclovir displays poor solubility in water and in lipid bilayers, which leads to poor drug levels at target sites after oral, local, or parenteral administration. In order to improve this lack of solubility, novel amphiphilic derivatives have been designed to form nanoparticles, which allow for the efficient encapsulation of this hydrophobic antiviral agent. Reformulation of drugs in liposomes has provided an opportunity to enhance the therapeutic indices of various agents mainly via alteration of their bio-distribution. Liposomal drug delivery systems have received considerable attention due to their immense advantages which include, effective encapsulation of both small and large molecules that have a wide range of hydrophobicity levels and pKa values, prolonging and targeting release of therapeutic agents by modification of liposomal surface and also minimising clinical drug dose thus reducing toxicity effects. Liposomes exhibit a number of special biological characteristics, including specific interactions with biological membranes and various cells, hence, liposomes are used as biocompatible carriers to improve delivery properties across mucus membranes. Mucoadhesive dosage forms may be designed to enable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcome. The aim of this study was to develop an acyclovir liposomal mucoadhesive film by actively encapsulating acyclovir into liposomes and preparing a mucoadhesive film to optimise delivery of acyclovir liposomes at target sites. To actively encapsulate acyclovir and prepare the acyclovir-containing liposomes, a comprehensive statistical methodology was used in optimising the liposome formulation to encapsulate acyclovir. Central composite design was used as the response surface methodology statistical tool to design and develop an optimised method for active encapsulation of acyclovir into liposomes. The predicted optimised encapsulation parameters were incubation temperature of 60 °C and incubation time of 45 minutes. The mean percentage encapsulation calculated was 27.72%. The overall average size of the liposomes was 99.5 nm with a narrow distribution polydispersity index of 0.105 and were physically characterised as small unilamellar vesicles which possessed an average zeta potential of -45.6 mV. High Performance Liquid Chromatography (HPLC) was used to analyse and determine acyclovir drug content in the liposomes and drug release pattern from the mucoadhesive film. Polyvinyl-pyrrolidone (PVP) and Polyethylene glycol (PEG) were used in the preparation of mucoadhesive film, in which the acyclovir encapsulated liposomes were incorporated. The average amount of acyclovir drug content quantified to be in 4 cm2 of the mucoadhesive film was 36.8543 μg. The average tensile strength of the mucoadhesive film was determined to be 3.06 N/mm2 with an elongation percentage of 4.54%. The toughness of the film was 71.50 N.mm and the force required to rupture film was 16.49 N. The work and maximum force required to detach the mucoadhesive film from the glass side was 2.58 N.mm and 11615.32 mN, respectively. A Franz diffusion cell was used to perform acyclovir drug release studies from the mucoadhesive film and a commercial brand of acyclovir cream (Acitop®). Percentage acyclovir drug release from the film and cream was plotted against time using Sigmaplot® software version 13 following First order, Peppas, Hixon and Crowell, Higuchi (Square Root Time) and Bakers and Lonsdale mathematical models. The mucoadhesive film acyclovir attained the highest correlation coefficient r2 of 0.9879 following the Baker & Lonsdale mathematical model which describes controlled drug release from spherical matrices hence fits the model as the acyclovir is encapsulated in liposomes which are incorporated in the polymer mucoadhesive film. And the acyclovir cream (Acitop®) attained the highest correlation coefficient r2 of 0.9944 following the Peppas mathematical model. The Peppas model has been used to describe drug release from various release dosage forms when there is more than one type of dosage release or when release mechanism is not well known. One assumption of this model is that drug release occurs in one dimension, which is a suitable release profile for the cream as it is absorbed through the skin in one dimension when applied topically. There was significant difference between the drug release data for the mucoadhesive film and the acyclovir cream (Acitop®). A physically stable mucoadhesive film containing acyclovir-loaded liposomes was developed.