Predictive Models for Maximum Recommended Therapeutic Dose of Antiretroviral Drugs

A novel method for predicting maximum recommended therapeutic dose (MRTD) is presented using quantitative structure property relationships (QSPRs) and artificial neural networks (ANNs). MRTD data of 31 structurally diverse Antiretroviral drugs (ARVs) were collected from FDA MRTD Database or package inserts. Molecular property descriptors of each compound, that is, molecular mass, aqueous solubility, lipophilicity, biotransformation half life, oxidation half life, and biodegradation probability were calculated from their SMILES codes. A training set (n = 23) was used to construct multiple linear regression and back propagation neural network models. The models were validated using an external test set (n = 8) which demonstrated that MRTD values may be predicted with reasonable accuracy. Model predictability was described by root mean squared errors (RMSEs), Kendall's correlation coefficients (tau), P-values, and Bland Altman plots for method comparisons. MRTD was predicted by a 6-3-1 neural network model (RMSE = 13.67, tau = 0.643, P = 0.035) more accurately than by the multiple linear regression (RMSE = 27.27, tau = 0.714, P = 0.019) model. Both models illustrated a moderate correlation between aqueous solubility of antiretroviral drugs and maximum therapeutic dose. MRTD prediction may assist in the design of safer, more effective treatments for HIV infection

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology.

Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future

A physiologically based pharmacokinetic model to characterise the association between CYP2B6 polymorphisms and efavirenz pharmacokinetics in pregnancy

A research report submitted to the faculty of health science, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of MSC MED pharmaceutical affairsMT201

Physiologically based pharmacokinetic modelling to investigate the impact of aging on drug pharmacokinetics and drug-drug interaction magnitudes in aging people living with HIV

People living with HIV (PLWH) are aging but are often excluded from clinical studies because of pragmatical and ethical concerns. Therefore, the effect of aging on the pharmacokinetics and drug-drug interaction (DDI) magnitudes of antiretroviral drugs remain uncertain. Consequently, clinical guidance regarding dose adjustment for antiretroviral drugs and the clinical management of DDIs with advanced aging are missing. Studies presented in this thesis combined clinically observed data with physiologically based pharmacokinetic (PBPK) modelling to investigate the continuous effect of aging on drug pharmacokinetics and DDI magnitudes. The PBPK model was developed in the mathematical programming language Matlab®. A virtual population considering age-related changes in demographics, physiology, and biology informed the model. Clinically observed data of ten non-HIV drugs being commonly administered as comedications to aging PLWH were used to verify the predictive power of the PBPK model to simulate drug disposition in the elderly. Extrapolating the pharmacokinetics of all investigated ten drugs across adulthood (20 to 99 years) elucidated that the progressively decreasing drug clearance drove age-related pharmacokinetic changes, which itself was caused by the decline of the hepatic and renal blood flow and the glomerular filtration rate. Age-dependent pharmacokinetic alterations were independent of drug characteristics. Additional clinical data of 52 drugs obtained from young and elderly individuals verified this general model-based hypothesis. Concentration-time profiles of ten antiretroviral drugs, belonging to the current first-line treatment, were obtained in two clinical studies including PLWH at least 55 years, who participated in the Swiss HIV Cohort Study. These clinically observed data were generally predicted within the 95% confidence interval of the PBPK model, demonstrating the ability of the used approach to predict real-life plasma concentrations from PLWH, who had a declined kidney function (e.g. the glomerular filtration rate was 65.6 ± 19.2 mL/min/1.73m²) and common comorbidities (e.g. hypertension). Age-related pharmacokinetic changes of antiretroviral drugs across adulthood were found to be similar to non-HIV drugs, indicating a marginal increase in antiretroviral drug exposure with advanced aging. One of the conducted clinical studies in PLWH at least 55 years was designed to investigate DDI magnitudes between amlodipine, atorvastatin, or rosuvastatin and a dolutegravir (no interaction expected) or a boosted darunavir (high interaction potential) containing antiretroviral regimen. The comparison with historical data obtained in young PLWH aged 20 to 50 years yielded no changes in the DDI magnitudes between both investigated age groups. These clinically observed data were used to verify DDI simulations of the developed PBPK framework in the elderly and subsequently DDI magnitudes were predicted across the entire adult lifespan. The model indicated that DDI magnitudes were unchanged across adulthood regardless of the involved drugs, the DDI mechanism, or the sex of the investigated individual. This general model-based hypothesis was verified with independent clinically observed data from 17 DDIs. As DDI magnitudes are not impacted by aging, static methods can be applied to predict DDI magnitudes in elderly patients, who receive two drugs with an uncharacterized DDI magnitude. Predictions are based on the fraction of metabolism by a specific enzyme and the strength of an inhibitor or inducer. In contrast to the PBPK approach, the static method provides a more straightforward supportive tool to rationalize dose adjustments to overcome a given DDI. In conclusion, this thesis demonstrates marginal pharmacokinetic alterations of antiretroviral drugs and no age-related changes of DDI magnitudes. Therefore, a dose adjustment of antiretroviral drugs or a different management of DDIs in clinical practice are a priori not necessary when treating aging male and female PLWH in the absence of severe comorbidities. These general rules being broadly applicable to antiretroviral and non-HIV drugs support the overall care of elderly PLWH beyond HIV and therapies of future effective drugs

Pharmacometrics of dolutegravir and tenofovir: a quantitative approach to characterise drug-drug interactions, pharmacogenetics and optimise treatment

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

Population pharmacokinetic modelling to address the gaps in knowledge of commonly used HIV and TB drugs in children

The epidemiology of HIV and TB are overlapping, particularly in sub-Saharan Africa, and TB infection remains common in HIV-positive children. The combined administration of anti-tubercular and antiretroviral therapies(ART) may lead to drug-drug interactions potentially needing to be addressed with the adjustment of doses. This thesis assessed the pharmacokinetics of abacavir and ethambutol and evaluated the influence of covariates such as age and concomitant medication on the PK parameters across different studies using nonlinear mixed-effects modelling. The models developed were used to estimate area under the concentration-time curve (AUC) and maximum concentrations (Cmax) achieved with the currently-recommended weight-adjusted doses. A web-based paediatric dosing tool, which is meant to be used as a first step in the design of clinical trials for paediatric dosing was also developed. The model describing the pharmacokinetics of abacavir found: a) abacavir exposure to be 18.4% larger (CI:7.50-32.2) after the first dose of ART compared to abacavir co-treated with standard lopinavir/ritonavir for over 7 days, possibly indicating that clearance is induced with time on ART, b) malnourished HIV infected children had much higher exposures but this effect waned with a half-life of 12.2 (CI: 9.87-16.8) days as children stayed on nutritional rehabilitation and recovered, c). during co-administration of rifampicin-containing antituberculosis treatment and super-boosted lopinavir/ritonavir, abacavir exposure was decreased by 29.4% (CI: 24.3-35.8), d) children receiving efavirenz had 12.1% (CI: 2.57-20.1) increased abacavir clearance compared to standard lopinavir/ritonavir. The effects did not result in abacavir exposures lower or higher than those reported in adults and are not likely to be clinically important. The ethambutol model found lower concentrations than those reported in adults. The predicted ethambutol median (IQR) Cmax was 1.66 (1.21-2.15) mg/L for children on ethambutol with or without ART (excluding super-boosted lopinavir/ritonavir) and 0.882 (0.669-1.28) mg/L for children on ethambutol with super-boosted lopinavir/ritonavir, these are below the lower limit of the recommended Cmax range of 2 mg/L. During co-administration with super-boosted lopinavir, ethambutol exposure was decreased by 32% (CI: 23.8-38.9), likely due to drug-drug interaction involving absorption, metabolism or elimination. Bioavailability was decreased in children who were administered ethambutol in a crushed form, with an estimate decrease of 30.8% at birth, and an increase of 9.6% for each year of age up to 3.2 years where bioavailability was now similar to children taking EMB full tablet. The developed paediatric dosing tool contains two major sections. a) the ‘generic module’ which uses allometric scaling -based predictions to explore the expected AUC for a generic drug, b) the ‘drug-specific module’ which can simulate entire pharmacokinetic profiles (concentration over time after dose) by using a drug-specific population pharmacokinetic model. In summary, under the current weight-adjusted doses, abacavir exposure remained within the adult recommended levels. Ethambutol dose adjustment would be required in order to achieve adult exposures. A web-based paediatric dosing tool that uses allometric scaling -based predictions as well as drug specific predictions based on published pharmacokinetic models was successfully developed

Therapeutic drug monitoring in patients with tuberculosis and concurrent medical problems

Introduction Therapeutic drug monitoring (TDM) has been recommended for treatment optimization in tuberculosis (TB) but is only is used in certain countries e.g. USA, Germany, the Netherlands, Sweden and Tanzania. Recently, new drugs have emerged and PK studies in TB are continuing, which contributes further evidence for TDM in TB. The aim of this review is to provide an update on drugs used in TB, treatment strategies for these drugs, and TDM to support broader implementation. Areas covered This review describes the different drug classes used for TB, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), along with their pharmacokinetics, dosing strategies, TDM and sampling strategies. Moreover, the review discusses TDM for patient TB and renal or liver impairment, patients co-infected with HIV or hepatitis, and special patient populations - children and pregnant women. Expert opinion TB treatment has a long history of using 'one size fits all.' This has contributed to treatment failures, treatment relapses, and the selection of drug-resistant isolates. While challenging in resource-limited circumstances, TDM offers the clinician the opportunity to individualize and optimize treatment early in treatment. This approach may help to refine treatment and thereby reduce adverse effects and poor treatment outcomes. Funding, training, and randomized controlled trials are needed to advance the use of TDM for patients with TB