The Impact of Paediatric Obesity on Drug Pharmacokinetics: A Virtual Clinical Trials Case Study with Amlodipine.

The incidence of paediatric obesity continues to rise worldwide and contributes to a range of diseases including cardiovascular disease. Obesity in children has been shown to impact upon the plasma concentrations of various compounds, including amlodipine. Nonetheless, information on the influence of obesity on amlodipine pharmacokinetics and the need for dose adjustment has not been studied previously. This study applied the physiologically based pharmacokinetic modelling and established a paediatric obesity population to assess the impact of obesity on amlodipine pharmacokinetics in children and explore the possible dose adjustments required to reach the same plasma concentration as non-obese paediatrics. The difference in predicted maximum concentration (Cmax) and area under the curve (AUC) were significant between children with and without obesity across the age group 2 to 18 years old when a fixed-dose regimen was used. On the contrary, a weight-based dose regimen showed no difference in Cmax between obese and non-obese from 2 to 9 years old. Thus, when a fixed-dose regimen is to be administered, a 1.25- to 1.5-fold increase in dose is required in obese children to achieve the same Cmax concentration as non-obese children, specifically for children aged 5 years and above.

Precision dosing of venlafaxine during pregnancy: a pharmacokinetics modelling approach.

OBJECTIVES: Venlafaxine exposure through gestation is affected by the longitudinal changes in maternal physiology. Confounding treatment is also the impact of CYP2D6 polymorphisms affecting plasma concentrations of venlafaxine. METHODS: A pharmacokinetic modelling approach was employed to assess variations in maternal and foetal cord venlafaxine levels throughout gestation and to identify appropriate doses to maintain venlafaxine levels within the therapeutic range. KEY FINDINGS: Throughout gestation, there was a significant decrease in simulated venlafaxine trough plasma concentrations in both extensive metaboliser (EM) and ultra-rapid metaboliser (UM) phenotypes. Approximately 70%-87% of EM and UM phenotypes exhibited trough venlafaxine plasma concentrations below the therapeutic level (<25 ng/ml), which increased to 96% at week 30. While for poor metabolizer (PM) phenotypes, the percentage was approximately 4%. CONCLUSION: The standard daily dose of 75 mg required adjustment for all phenotypes examined during gestation. A daily dose of 37.5-112.5 mg is appropriate for PM throughout pregnancy. For EM, a dose of 225 mg daily in the first trimester, 262.5 mg daily in the second trimester, and 375 mg daily in the third trimester is suggested to be optimal. For UM, a dose of 375 mg daily throughout gestation is suggested to be optimal.

The Application of Virtual Therapeutic Drug Monitoring to Assess the Pharmacokinetics of Imatinib in a Chinese Cancer Population Group.

PURPOSE: Imatinib is used in gastrointestinal stromal tumours (GIST) and chronic myeloid leukaemia (CML). Oncology patients demonstrate altered physiology compared to healthy adults, e.g. reduced haematocrit, increased α-1 acid glycoprotein, decreased albumin and reduced glomerular filtration rate (GFR), which may influence imatinib pharmacokinetics. Given that Chinese cancer patients often report raised imatinib plasma concentrations and wider inter-individual variability reported in trough concentration when compared to Caucasian cancer patients, therapeutic drug monitoring (TDM) has been advocated. METHOD: This study utilised a previously validated a Chinese cancer population and assessed the impact of imatinib virtual-TDM in Chinese and Caucasian cancer populations across a dosing range from 200-800 mg daily. RESULTS: Staged dose titration to 800 mg daily, resulted in recapitulation to within the target therapeutic range for 50 % (Chinese) and 42.1% (Caucasian) subjects possessing plasma concentration < 550 ng/mL when dosed at 400 mg daily. For subjects with plasma concentrations >1500 ng/mL when dosed at 400 mg daily, a dose reduction to 200 mg once daily was able to recover 67 % (Chinese) and 87.4 % (Caucasian) patients to the target therapeutic range. CONCLUSION: Virtual TDM highlights the benefit of pharmacokinetic modelling to optimising treatments in challenging oncology population groups.

Development of a novel polymer-based carrier for deformable liposomes for the controlled dermal delivery of naringenin.

In recent years, the incidence of skin cancer has increased worldwide, presenting a significant burden on healthcare services. Chemotherapy intervention is often not appropriate for all patients due to localized adverse effects on skin physiology. The aim of this study was, therefore, to consider the development of a novel phytochemical-based deformable liposomal formulation suspended in an aqueous gel for the controlled-release of naringenin. Naringenin is an antioxidant, free radical scavenger, anti-inflammatory agent, and immune system modulator thus may be potentially useful as a pharmacological anti-cancer agent. Formulated liposomes incorporating an increasing loading of Tween 20 (from 0% w/w to 10% w/w) demonstrated a significant decrease in deformability index (DI) (80.71 ± 2.02-59.17 ± 4.42 %), indicating an increase in elasticity. The release of naringenin over 24 h was directly affected by Tween-20 concentration, decreasing from 100.72%±4.98% to 79.53%±3.68% for 0% and 2% w/w Tween 20, respectively. Further, the incorporation of deformable liposomes into hydroxyethylcellulose (HEC) and hydroxypropyl methylcellulose (HPMC) gels resulting in a further retardation of naringenin release, 23.21%±1.17% and 19.83%±1.50%, respectively, over 24 h. Incubation of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-loaded liposomes with human dermal fibroblast (HDF) and keratinocyte cells demonstrated intracellular accumulation within 2 h, confirming deformable liposomes may be beneficial in improving drug penetration across dermal cells and would be valuable in emerging controlled-release formulations.

Precision dosing of methadone during pregnancy: A pharmacokinetics virtual clinical trials study.

BACKGROUND: Methadone use for the management of opioid dependency during pregnancy is commonplace. Methadone levels are altered during pregnancy due to changes in maternal physiology. Despite this, a paucity of data exist regarding the most appropriate optimal dosing regimens during pregnancy. METHODS: This study applied a pharmacokinetic modeling approach to examine gestational changes in R- and S-methadone concentrations in maternal plasma and fetal (cord) blood. This study did so to derive a theoretical optimal dosing regimen during pregnancy, and to identify the impact of Cytochromes P450 (CYP) 2B6 and 2C19 polymorphisms on methadone maternal and fetal pharmacokinetics. RESULTS: The study noted significant decreases in maternal R- and S-methadone plasma concentrations during gestation, with concomitant increases in fetal levels. At a dose of 90 mg once daily, 75% (R-) and 94% (S-) of maternal methadone trough levels were below the lower therapeutic window at term (week 40). The developed optimal dosing regimen escalated doses to 110 mg by week 5, followed by 10 mg increments every 5 weeks up to a maximum of 180 mg once daily near term. This increase resulted in 27% (R-) and 11% (S-) of subjects with trough levels below the lower therapeutic window at term. CYP2B6 poor metabolizers (PM) and either CYP2C19 extensive metabolizers (EM), PM, or ultra-rapid (UM) metabolizer phenotypes demonstrated statistically significant increases in concentrations when compared to their matched CYP2B6 EM counterparts. CONCLUSIONS: Specific and gestation-dependent dose titrations are required during pregnancy to reduce the risks associated with illicit drug use and to maintain fetal safety.

The Pharmacokinetics of Gefitinib in a Chinese Cancer Population Group: A Virtual Clinical Trials Population Study.

Gefitinib, a selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is used to treat non-small-cell lung cancer (NSCLC). Lung cancer rates are high in China and are expected to increase over the next decade. CYP 2D6 intermediate metaboliser (IM) phenotypes are more prevalent in the Chinese population compared to Caucasians; the increased risk of drug-drug interactions (DDI) with chemotherapy polypharmacy may lead to different clinical pharmacokinetics outcomes for Chinese patients. This study developed and validated a virtual Chinese cancer population for the pragmatic assessment of gefitinib DDI as a victim drug in Chinese and Caucasian cancer populations. When assessing the impact of 2D6 phenotypes on bupropion mediated CYP 2D6 DDI in Chinese cancer population, we found that AUC increased by at least 60% in extensive metabolizers (EM) and 30% in IM. As a result, fmCYP2D6 was reduced by 15% in IM in the presence of bupropion, translating into > 70% of EM subjects and > 48% of IM subjects with trough concentrations at steady state (Ctrough,ss) below the gefitinib target trough level. The PBPK model predicted that a 500 mg once daily dose in both EM and IM subjects successfully reduced the percent of subjects below the Ctrough,ss. Such changes in Ctrough,ss warrant further investigation and highlight the ability of pharmacokinetic modelling to investigate populations that may be difficult to recruit for traditional clinical studies.

The application of precision dosing in the use of sertraline throughout pregnancy for poor and ultrarapid metabolizer CYP 2C19 subjects: A virtual clinical trial pharmacokinetics study.

Sertraline is known to undergo changes in pharmacokinetics during pregnancy. CYP 2C19 has been implicated in the interindividual variation in clinical effect associated with sertraline activity. However, knowledge of suitable dose titrations during pregnancy and within CYP 2C19 phenotypes is lacking. A pharmacokinetic modeling virtual clinical trials approach was implemented to: (i) assess gestational changes in sertraline trough plasma concentrations for CYP 2C19 phenotypes, and (ii) identify appropriate dose titration strategies to stabilize sertraline levels within a defined therapeutic range throughout gestation. Sertraline trough plasma concentrations decreased throughout gestation, with maternal volume expansion and reduction in plasma albumin being identified as possible causative reasons. All CYP 2C19 phenotypes required a dose increase throughout gestation. For extensive metabolizer (EM) and ultrarapid metabolizer (UM) phenotypes, doses of 100-150 mg daily are required throughout gestation. For poor metabolizers (PM), 50 mg daily during trimester 1 followed by a dose of 100 mg daily in trimesters 2 and 3 are required.

Formulation and Bioequivalence Testing of Fixed-Dose Combination Orally Disintegrating Tablets for the Treatment of Tuberculosis in the Paediatric Population.

Tuberculosis (TB) is believed to affect around 10 million people worldwide. Treatment for TB includes isoniazid and rifampicin, with fixed-dose combination (FDC) recommended for improved patient compliance. Similarly, orally disintegrating tablets (ODTs) are an increasingly popular dosage form that aid compliance since they do not require swallowing. In this study ODTs of isoniazid and rifampicin, either as discrete or FDC doses, were formulated and bioequivalence between single and combination doses compared using in vitro and in silico approaches. Dissolution profiles were compared using FDA advised difference (f1) and similarity (f2) testing in biorelevant media. Rifampicin release from FDCs decreased by approximately 15% in fed-state media (failed f1 and f2), which was attributed to enhanced rifampicin degradation in the presence of isoniazid at lower pH. Apparent permeability (Papp) values derived from Caco-2 transport studies were included alongside dissolution results into a physiologically based pharmacokinetic (PBPK) model, to simulate in vivo bioavailability in healthy subjects. Models showed no difference in bioavailability between formulations or dosing (fasted or fed) state, despite the failures in dissolution-based bioequivalence testing, highlighting shortcomings in f1 and f2 assessment and the strength of PBPK models.

Drug dosing during pregnancy-opportunities for physiologically based pharmacokinetic models.

Drugs can have harmful effects on the embryo or the fetus at any point during pregnancy. Not all the damaging effects of intrauterine exposure to drugs are obvious at birth, some may only manifest later in life. Thus, drugs should be prescribed in pregnancy only if the expected benefit to the mother is thought to be greater than the risk to the fetus. Dosing of drugs during pregnancy is often empirically determined and based upon evidence from studies of non-pregnant subjects, which may lead to suboptimal dosing, particularly during the third trimester. This review collates examples of drugs with known recommendations for dose adjustment during pregnancy, in addition to providing an example of the potential use of PBPK models in dose adjustment recommendation during pregnancy within the context of drug-drug interactions. For many drugs, such as antidepressants and antiretroviral drugs, dose adjustment has been recommended based on pharmacokinetic studies demonstrating a reduction in drug concentrations. However, there is relatively limited (and sometimes inconsistent) information regarding the clinical impact of these pharmacokinetic changes during pregnancy and the effect of subsequent dose adjustments. Examples of using pregnancy PBPK models to predict feto-maternal drug exposures and their applications to facilitate and guide dose assessment throughout gestation are discussed.

Precision dosing-based optimisation of paroxetine during pregnancy for poor and ultrarapid CYP2D6 metabolisers: a virtual clinical trial pharmacokinetics study.

OBJECTIVE: Paroxetine has been demonstrated to undergo gestation-related reductions in plasma concentrations, to an extent which is dictated by the polymorphic state of CYP 2D6. However, knowledge of appropriate dose titrations is lacking. METHODS: A pharmacokinetic modelling approach was applied to examine gestational changes in trough plasma concentrations for CYP 2D6 phenotypes, followed by necessary dose adjustment strategies to maintain paroxetine levels within a therapeutic range of 20-60 ng/ml. KEY FINDINGS: A decrease in trough plasma concentrations was simulated throughout gestation for all phenotypes. A significant number of ultrarapid (UM) phenotype subjects possessed trough levels below 20 ng/ml (73-76%) compared to extensive metabolisers (EM) (51-53%). CONCLUSIONS: For all phenotypes studied, there was a requirement for daily doses in excess of the standard 20 mg dose throughout gestation. For EM, a dose of 30 mg daily in trimester 1 followed by 40 mg daily in trimesters 2 and 3 is suggested to be optimal. For poor metabolisers (PM), a 20 mg daily dose in trimester 1 followed by 30 mg daily in trimesters 2 and 3 is suggested to be optimal. For UM, a 40 mg daily dose throughout gestation is suggested to be optimal.

A dynamic perfusion based blood-brain barrier model for cytotoxicity testing and drug permeation.

The blood-brain barrier (BBB) serves to protect and regulate the CNS microenvironment. The development of an in-vitro mimic of the BBB requires recapitulating the correct phenotype of the in-vivo BBB, particularly for drug permeation studies. However the majority of widely used BBB models demonstrate low transendothelial electrical resistance (TEER) and poor BBB phenotype. The application of shear stress is known to enhance tight junction formation and hence improve the barrier function. We utilised a high TEER primary porcine brain microvascular endothelial cell (PBMEC) culture to assess the impact of shear stress on barrier formation using the Kirkstall QuasiVivo 600 (QV600) multi-chamber perfusion system. The application of shear stress resulted in a reorientation and enhancement of tight junction formation on both coverslip and permeable inserts, in addition to enhancing and maintaining TEER for longer, when compared to static conditions. Furthermore, the functional consequences of this was demonstrated with the reduction in flux of mitoxantrone across PBMEC monolayers. The QV600 perfusion system may service as a viable tool to enhance and maintain the high TEER PBMEC system for use in in-vitro BBB models.

Quetiapine dose optimisation during gestation: a pharmacokinetic modelling study.

OBJECTIVES: The second-generation antipsychotic quetiapine has been demonstrated to undergo gestation-related changes in pharmacokinetics. This study applied pharmacokinetic modelling principles to investigate the mechanism of these changes and to propose new dosing strategies to counteract these changes. METHODS: A pharmacokinetic modelling approach was implemented using virtual population groups. Changes in quetiapine trough plasma concentration during gestation were quantified across all trimesters, and dose adjustment strategies were applied to counteract these changes by targeting a therapeutic range of 50-500 ng/ml throughout gestation. KEY FINDINGS: The application of the model during gestation predicted a decrease in trough concentration. A maximum decrease of 58% was predicted during trimester 2, and being associated with a statistically significant decrease in oral clearance at gestation week 25, 204 l/h ± 100.8 l/h compared with non-pregnant subjects, 121.9 l/h ± 51.8 l/h. A dosing optimisation strategy identified that dose increases to 500-700 mg twice daily would result in 32-55% of subjects possessing trough concentration in excess of 50 ng/ml. CONCLUSIONS: Quetiapine doses in pregnancy should be increased to 500-700 mg twice daily to counteract a concomitant increase in metabolic clearance, increase in volume of distribution and decrease in plasma protein binding.

The optimization of methadone dosing whilst treating with rifampicin: A pharmacokinetic modeling study.

BACKGROUND: The use of oral methadone in opioid substitution treatment (OST) for the management of opioid use disorder is established clinical practice. Confounding treatment is the increased risks of contracting Mycobacterium tuberculosis, the mainstay treatment of which incorporates the potent CYP 2B6 inducer rifampicin. METHODS: This study applied pharmacokinetic modelling using virtual clinical trials, to pharmacokinetically quantify the extent and impact of rifampicin-mediated drug-drug interactions (DDI) on methadone plasma concentrations. An R-methadone model was developed and validated against 11 retrospective clinical studies prior to use in all subsequent studies. The aims were to investigate: (i) the impact of the DDI on daily methadone doses of 60 mg, 90 mg and 120 mg; (ii) dose escalation during rifampicin and (iii) dose reduction following rifampicin cessation. RESULTS: A dose increase to 160 mg daily during rifampicin treatment phases was required to maintain peak methadone plasma concentrations within a derived therapeutic window of 80-700 ng/mL. Dose escalation prior to rifampicin initiation was not required and resulted in an increase in subjects with supra-therapeutic concentrations. However, during rifampicin cessation, a dose reduction of 10 mg every 2 days commencing prior to rifampicin cessation, ensured that most patients possessed a peak methadone plasma concentration within an optimal therapeutic window. IMPLICATIONS: Rifampicin significantly alters methadone plasma concentrations and necessitates dose adjustments. Daily doses of almost double those used perhaps more commonly in clinical practice are required for optimal plasma concentration and careful consideration of dose reduction strategies would be required during the deinduction phase.

High-throughput screening of excipients with a biological effect: a kinetic study on the effects of surfactants on efflux-mediated transport.

OBJECTIVE: In this study, we develop and apply a high-throughput screening protocol to investigate the activity of non-ionic surfactants, with a broad range of hydrophilic-lipophilic balance values, against ABCB1-mediated efflux transport and ABCC2-mediated efflux transport. METHODS: Caco-2 cells were grown for 7 days in 96-well plates, then washed and incubated with the test materials for 2 h in the presence of 2.5 µm of either rhodamine 123 (R-123) or 5(6)-Carboxy-2',7' dichlorofluorescein diacetate as probes of ABCB1 and ABCC2, respectively. KEY FINDINGS: Of the surfactants tested, no activity against ABCC2 was detected and all surfactants showing efficacy against ABCB1 had a HLB value of 22 or below. Inhibition of ABCB1 was seen in the order of efficacy to be poloxamer 335 > poloxamer 40 > Crovol A-70 > Myrj S-40 > poloxamer 184 > poloxamer 182 > Etocas 40 > Tween 20 > Etocas 29 > Tween 80 > Acconon C-44 > Span 20. With regard to this inhibition, the distribution of hydrophilic regions is more important than the HLB value. CONCLUSION: This work demonstrates a high-throughput protocol for detecting materials that can modulate ABCB1-mediated efflux. These surfactants could be exploited to improve oral delivery of drugs prone to efflux.

Dose Optimization of Chloroquine by Pharmacokinetic Modeling During Pregnancy for the Treatment of Zika Virus Infection.

The insidious nature of Zika virus (ZIKV) infections can have a devastating consequence for fetal development. Recent reports have highlighted that chloroquine (CQ) is capable of inhibiting ZIKV endocytosis in brain cells. We applied pharmacokinetic modeling to develop a predictive model for CQ exposure to identify an optimal maternal/fetal dosing regimen to prevent ZIKV endocytosis in brain cells. Model validation used 13 nonpregnancy and 3 pregnancy clinical studies, and a therapeutic CQ plasma window of 0.3-2 µM was derived. Dosing regimens used in rheumatoid arthritis, systemic lupus erythematosus, and malaria were assessed for their ability to target this window. Dosing regimen identified that weekly doses used in malaria were not sufficient to reach the lower therapeutic window; however, daily doses of 150 mg achieved this therapeutic window. The impact of gestational age was further assessed and culminated in a final proposed regimen of 600 mg on day 1, 300 mg on day 2 and 3, and 150 mg thereafter until the end of trimester 2, which resulted in maintaining 65% and 94% of subjects with a trough plasma concentration above the lower therapeutic window on day 6 and at term, respectively.

Clopidogrel Pharmacokinetics in Malaysian Population Groups: The Impact of Inter-Ethnic Variability.

Malaysia is a multi-ethnic society whereby the impact of pharmacogenetic differences between ethnic groups may contribute significantly to variability in clinical therapy. One of the leading causes of mortality in Malaysia is cardiovascular disease (CVD), which accounts for up to 26% of all hospital deaths annually. Clopidogrel is used as an adjunct treatment in the secondary prevention of cardiovascular events. CYP2C19 plays an integral part in the metabolism of clopidogrel to the active metabolite clopi-H4. However, CYP2C19 genetic polymorphism, prominent in Malaysians, could influence target clopi-H4 plasma concentrations for clinical efficacy. This study addresses how inter-ethnicity variability within the Malaysian population impacts the attainment of clopi-H4 target plasma concentration under different CYP2C19 polymorphisms through pharmacokinetic (PK) modelling. We illustrated a statistically significant difference (P < 0.001) in the clopi-H4 Cmax between the extensive metabolisers (EM) and poor metabolisers (PM) phenotypes with either Malay or Malaysian Chinese population groups. Furthermore, the number of PM individuals with peak clopi-H4 concentrations below the minimum therapeutic level was partially recovered using a high-dose strategy (600 mg loading dose followed by a 150 mg maintenance dose), which resulted in an approximate 50% increase in subjects attaining the minimum clopi-H4 plasma concentration for a therapeutic effect.

The impact of CYP2B6 polymorphisms on the interactions of efavirenz with lumefantrine: Implications for paediatric antimalarial therapy.

Lumefantrine is a widely used antimalarial in children in sub-Saharan Africa and is predominantly metabolised by CYP3A4. The concomitant use of lumefantrine with the antiretroviral efavirenz, which is metabolised by CYP2B6 and is an inducer of CYP3A4, increases the risk of lumefantrine failure and can result in an increased recrudescence rate in HIV-infected children. This is further confounded by CYP2B6 being highly polymorphic resulting in a 2-3 fold higher efavirenz plasma concentration in polymorphic subjects, which enhances the potential for an efavirenz-lumefantrine drug-drug interaction (DDI). This study developed a population-based PBPK model capable of predicting the impact of efavirenz-mediated DDIs on lumefantrine pharmacokinetics in African paediatric population groups, which also considered the polymorphic nature of CYP2B6. The validated model demonstrated a significant difference in lumefantrine target day 7 concentrations (Cd7) in the presence and absence of efavirenz and confirmed the capability of efavirenz to initiate this DDI. This was more apparent in the *6/*6 compared to *1/*1 population group and resulted in a significantly lower (P < 0.001) lumefantrine Cd7. A prospective change in dosing schedule from 3-days to 7-days resulted in a greater number of *6/*6 subjects (28-57%) attaining the target Cd7 across age bands (0.25-13 years), with the greatest increase evident in the 1-4 year old group (3-day: 1%; 7-day: 28%).

Application of Pharmacokinetics Modelling to Predict Human Exposure of a Cationic Liposomal Subunit Antigen Vaccine System.

The pharmacokinetics of a liposomal subunit antigen vaccine system composed of the cationic lipid dimethyldioctadecylammonium bromide (DDA) and the immunostimulatory agent trehalose 6,6-dibehenate (TDB) (8:1 molar ratio) combined with the Ag85B-ESAT-6 (H1) antigen were modelled using mouse in-vivo data. Compartment modelling and physiologically based pharmacokinetics (PBPK) were used to predict the administration site (muscle) and target site (lymph) temporal concentration profiles and factors governing these. Initial estimates using compartmental modelling established that quadriceps pharmacokinetics for the liposome demonstrated a long half-life (22.6 days) compared to the associated antigen (2.62 days). A mouse minimal-PBPK model was developed and successfully predicted quadriceps liposome and antigen pharmacokinetics. Predictions for the popliteal lymph node (PLN) aligned well at earlier time-points. A local sensitivity analysis highlighted that the predicted AUCmuscle was sensitive to the antigen degradation constant kdeg (resulting in a 3-log change) more so than the fraction escaping the quadriceps (fe) (resulting in a 10-fold change), and the predicted AUCPLN was highly sensitive to fe. A global sensitivity analysis of the antigen in the muscle demonstrated that model predictions were within the 50th percentile for predictions and showed acceptable fits. To further translate in-vitro data previously generated by our group, the mouse minimal-PBPK model was extrapolated to humans and predictions made for antigen pharmacokinetics in muscle and PLN. Global analysis demonstrated that both kdeg and fe had a minimal impact on the resulting simulations in the muscle but a greater impact in the PLN. In summary, this study has predicted the in-vivo fate of DDA:TDB:H1 in humans and demonstrated the roles that formulation degradation and fraction escaping the depot site can play upon the overall depot effect within the site of administration.

The application of physiologically based pharmacokinetic modelling to assess the impact of antiretroviral-mediated drug-drug interactions on piperaquine antimalarial therapy during pregnancy.

Antimalarial therapy during pregnancy poses important safety concerns due to potential teratogenicity and maternal physiological and biochemical changes during gestation. Piperaquine (PQ) has gained interest for use in pregnancy in response to increasing resistance towards sulfadoxine-pyrimethamine in sub-Saharan Africa. Coinfection with HIV is common in many developing countries, however, little is known about the impact of antiretroviral (ARV) mediated drug-drug interaction (DDI) on piperaquine pharmacokinetics during pregnancy. This study applied mechanistic pharmacokinetic modelling to predict pharmacokinetics in non-pregnant and pregnant patients, which was validated in distinct customised population groups from Thailand, Sudan and Papua New Guinea. In each population group, no significant differences in day 7 concentrations were observed during different gestational weeks (GW) (weeks 10-40), supporting the notion that piperaquine is safe throughout pregnancy with consistent pharmacokinetics, although possible teratogenicity may limit this. Antiretroviral-mediated DDIs (efavirenz and ritonavir) had moderate effects on piperaquine during different gestational weeks with a predicted AUCratio in the range 0.56-0.8 and 1.64-1.79 for efavirenz and ritonavir, respectively, over GW 10-40, with a reduction in circulating human serum albumin significantly reducing the number of subjects attaining the day 7 (post-dose) therapeutic efficacy concentrations under both efavirenz and ritonavir DDIs. This present model successfully mechanistically predicted the pharmacokinetics of piperaquine in pregnancy to be unchanged with respect to non-pregnant women, in the light of factors such as malaria/HIV co-infection. However, antiretroviral-mediated DDIs could significantly alter piperaquine pharmacokinetics. Further model refinement will include collation of relevant physiological and biochemical alterations common to HIV/malaria patients.

Development of a paediatric physiologically based pharmacokinetic model to assess the impact of drug-drug interactions in tuberculosis co-infected malaria subjects: A case study with artemether-lumefantrine and the CYP3A4-inducer rifampicin.

The fixed dosed combination of artemether and lumefantrine (AL) is widely used for the treatment of malaria in adults and children in sub-Sahara Africa, with lumefantrine day 7 concentrations being widely used as a marker for clinical efficacy. Both are substrates for CYP3A4 and susceptible to drug-drug interactions (DDIs); indeed, knowledge of the impact of these factors is currently sparse in paediatric population groups. Confounding malaria treatment is the co-infection of patients with tuberculosis. The concomitant treatment of AL with tuberculosis chemotherapy, which includes the CYP3A4 inducer rifampicin, increases the risk of parasite recrudescence and malaria treatment failure. This study developed a population-based PBPK model for AL in adults capable of predicting the pharmacokinetics of AL under non-DDI and DDI conditions, as well as predicting AL pharmacokinetics in paediatrics of 2-12years of age. The validated model was utilised to assess the concomitant treatment of rifampicin and lumefantrine under standard body-weight based treatment regimens for 2-5year olds, and demonstrated that no subjects attained the target day 7 concentration (Cd7) of 280ng/mL, highlighting the importance of this DDI and the potential risk of malaria-TB based DDIs. An adapted 7-day treatment regimen was simulated and resulted in 63% and 74.5% of subjects attaining the target Cd7 for 1-tablet and 2-tablet regimens respectively.