Julie Bertrand

Population pharmacokinetic-pharmacogenetic study of nevirapine in HIV-infected Cambodian patients

ABSTRACT The aims of this ANRS12154 open-label, single-center, multiple-dose pharmacokinetic study were to characterize nevirapine pharmacokinetics in a Cambodian population of HIV-infected patients and to identify environmental and genetic factors of variability, focusing on the CYP2B6, CYP3A5, and ABCB1 (MDR1) genes. A total of 170 Cambodian HIV-infected patients were included. Nevirapine trough concentrations were measured after 18 and 36 months of starting antiretroviral treatment and in samples drawn during a dosing interval in a subset of 10 patients. All data were analyzed by nonlinear mixed-effects modeling. The effect of covariates was investigated using the population pharmacokinetic model. Patients carrying homozygous loss-of-function alleles CYP3A5 6986A>G, CYP2B6 516G>T, CYP2B6 1459C>T, and ABCB1 3435C>T represent 42.4%, 9.2%, 0%, and 18% of the population, respectively. The median nevirapine trough concentrations did not differ after 18 and 36 months of treatment (5,705 ng/ml [range, ≤50 to 13,871] and 5,709 ng/ml [range, ≤50 to 15,422], respectively). Interpatient and intrapatient variabilities of nevirapine apparent clearance were 28% and 17%, respectively. CYP2B6 516G>T and creatinine clearance were found to significantly affect nevirapine apparent clearance. The estimated nevirapine apparent clearances were 2.95 liters/h, 2.62 liters/h, and 1.86 liters/h for CYP2B6 516GG, CYP2B6 516GT, and CYP2B6 516TT genotypes, respectively. The impact of creatinine clearance was small. This study demonstrates that 95% of the patients had sustained nevirapine exposure well above the 3,000-ng/ml threshold. Nevirapine clearance was shown to be affected by CYP2B6 516G>T genetic polymorphism and creatinine clearance, although this explained only part of the interpatient variability, which remains low compared to that for other antiretroviral drugs.

Dependence of Efavirenz- and Rifampicin-Isoniazid–Based Antituberculosis Treatment Drug-Drug Interaction on CYP2B6 and NAT2 Genetic Polymorphisms: ANRS 12154 Study in Cambodia

We investigated the population pharmacokinetics and pharmacogenetics of efavirenz in 307 patients coinfected with human immunodeficiency virus and tuberculosis and included in the Cambodian Early vs Late Initiation of Antiretrovirals trial (CAMELIA) in Cambodia. Efavirenz (600 mg/d) and stavudine plus lamivudine were administered in addition to standard antituberculosis treatment, including rifampicin and isoniazid. Blood samples were obtained a mean of 14 hours after efavirenz intake at weeks 2 and 6 after initiation of efavirenz and weeks 22 (efavirenz plus antituberculosis drugs) and 50 (efavirenz alone) after initiation of antituberculosis treatment. Ten patients participated in an extensive pharmacokinetic study after week 50. CYP2B6 G516T and C485-18T polymorphisms were the most significant covariates, with weight showing a significant minor effect. Change in efavirenz apparent clearance in patients taking both efavirenz and antituberculosis treatment was highly dependent on NAT2 polymorphism, as a possible surrogate of isoniazid exposure. Patients carrying the CYP2B6 516 TT genotype and slow-acetylation NAT2 phenotype had the lowest efavirenz apparent clearance. These data suggest that the inducing effect of rifampicin is counterbalanced by a concentration-dependant inhibitory effect of isoniazid on efavirenz clearance.

Multiple genetic variants predict steady-state nevirapine clearance in HIV-infected Cambodians

Objective In a previous analysis involving protocol ANRS 12154, interindividual variability in steady-state nevirapine clearance among HIV-infected Cambodians was partially explained by CYP2B6 516G→T (CYP2B6*6). Here, we examine whether additional genetic variants predict nevirapine clearance in this cohort. Methods Analyses included Phnom Penh ESTHER (Ensemble pour une Solidarité Thérapeutique Hospitalière en Réseau) cohort participants who had consented for genetic testing. All participants were receiving nevirapine plus two nucleoside analogs. The mean individual nevirapine clearance estimates were derived from a population model developed on nevirapine concentrations at 18 and 36 months of therapy. Polymorphisms were assayed in ABCB1, CYP2A6, CYP2B6, CYP2C19, CYP3A4, CYP3A5, and NR1I2. Results Of 198 assayed loci, 130 were polymorphic. Among 129 individuals with evaluable genetic data, nevirapine clearance ranged from 1.06 to 5.00 l/h in 128 individuals and was 7.81 l/h in one individual. In bivariate linear regression, CYP2B6 516G→T (CYP2B6*6) was associated with lower nevirapine clearances (P=3.5×10−6). In a multivariate linear regression model conditioned on CYP2B6 516G→T, independent associations were identified with CYP2B6 rs7251950, CYP2B6 rs2279343, and CYP3A4 rs2687116. The CYP3A4 association disappeared after censoring the outlier clearance value. A model that included CYP2B6 516G→T (P=1.0×10−9), rs7251950 (P=4.8×10−5), and rs2279343 (P=7.1×10−5) explained 11% of interindividual variability in nevirapine clearance. Conclusion Among HIV-infected Cambodians, several CYP2B6 polymorphisms were associated independently with steady-state nevirapine clearance. The prediction of nevirapine clearance was improved by considering several polymorphisms in combination.

Can a Flavored Spray (Pill Glide) Help Children Swallow Their Medicines? A Pilot Study

Pediatric pharmacists are constantly faced with the challenges of supporting children and caregivers for whom the difficulties of swallowing medicines can be a daily struggle. Most medicines are only available as tablets and capsules, and where liquid alternatives exist, these products often have issues with palatability and high costs. The objective of this study was to evaluate whether the swallowing spray, Pill Glide, could help children in taking their solid and liquid medicines. This open label pilot study compared the spray with a behavioral approach alone, the current standard of care at the pediatric hospital. Patients were children on long-term drug therapies, either transitioning from liquid preparations to tablets and capsules, or known to be experiencing swallowing difficulties. Using age-adapted diaries, patients self-reported the difficulty of taking medicines on a 6-point hedonic scale for 2 weeks before the intervention, and then for 1 week while using Pill Glide. Data were analyzed from 10 children aged 6 to 16 years, with an average burden of 3.5 tablets per day. Pill Glide (strawberry was the most popular flavor) was shown to significantly decrease the overall medicine taking difficulty score by 0.93 (range, 0.33–1.53), almost 1 hedonic face point on the scale used (P = .002). There was insufficient data for liquid medicines. Pill Glide could help children with pill swallowing, thus improving patient acceptability of medicines and potentially adherence. It could also be implemented as a useful cost-saving intervention because solid dosage forms are cheaper.

Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer’s disease

See Caravaggio and Graff-Guerrero (doi:10.1093/awx023) for a scientific commentary on this article.Antipsychotic drugs, originally developed to treat schizophrenia, are used to treat psychosis, agitation and aggression in Alzheimers disease. In the absence of dopamine D2/3 receptor occupancy data to inform antipsychotic prescribing for psychosis in Alzheimers disease, the mechanisms underpinning antipsychotic efficacy and side effects are poorly understood. This study used a population approach to investigate the relationship between amisulpride blood concentration and central D2/3 occupancy in older people with Alzheimers disease by combining: (i) pharmacokinetic data (280 venous samples) from a phase I single (50 mg) dose study in healthy older people (n = 20, 65-79 years); (ii) pharmacokinetic, 18F-fallypride D2/3 receptor imaging and clinical outcome data on patients with Alzheimers disease who were prescribed amisulpride (25-75 mg daily) to treat psychosis as part of an open study (n = 28; 69-92 years; 41 blood samples, five pretreatment scans, 19 post-treatment scans); and (iii) 18F-fallypride imaging of an antipsychotic free Alzheimers disease control group (n = 10, 78-92 years), to provide additional pretreatment data. Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side effects (Simpson Angus Scale scores > 3). Average steady state blood levels were low (71 ± 30 ng/ml), and associated with high D2/3 occupancies (65 ± 8%, caudate; 67 ± 11%, thalamus; 52 ± 11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20 ng/ml and D2/3 occupancies of 43% (caudate), 25% (putamen), 43% (thalamus). Extrapyramidal side effects (n = 7) emerged at a threshold concentration of 60 ng/ml, and D2/3 occupancies of 61% (caudate), 49% (putamen) and 69% (thalamus). This study has established that, as in schizophrenia, there is a therapeutic window of D2/3 receptor occupancy for optimal treatment of psychosis in Alzheimers disease. We have also shown that occupancies within and beyond this window are achieved at very low amisulpride doses in Alzheimers disease due to higher than anticipated occupancies for a given blood drug concentration. Our findings support a central pharmacokinetic contribution to antipsychotic sensitivity in Alzheimers disease and implicate the blood-brain barrier, which controls central drug access. Whether high D2/3 receptor occupancies are primarily accounted for by age- or disease-specific blood-brain barrier disruption is unclear, and this is an important future area of future investigation, as it has implications beyond antipsychotic prescribing.

Comparison of Nonlinear Mixed Effects Models and Noncompartmental Approaches in Detecting Pharmacogenetic Covariates

Genetic data is now collected in many clinical trials, especially in population pharmacokinetic studies. There is no consensus on methods to test the association between pharmacokinetics and genetic covariates. We performed a simulation study inspired by real clinical trials, using the pharmacokinetics (PK) of a compound under development having a nonlinear bioavailability along with genotypes for 176 single nucleotide polymorphisms (SNPs). Scenarios included 78 subjects extensively sampled (16 observations per subject) to simulate a phase I study, or 384 subjects with the same rich design. Under the alternative hypothesis (H1), six SNPs were drawn randomly to affect the log-clearance under an additive linear model. For each scenario, 200 PK data sets were simulated under the null hypothesis (no gene effect) and H1. We compared 16 combinations of four association tests, a stepwise procedure and three penalised regressions (ridge regression, Lasso, HyperLasso), applied to four pharmacokinetic phenotypes, two observed concentrations, area under the curve estimated by noncompartmental analysis and model-based clearance. The different combinations were compared in terms of true and false positives and probability to detect the genetic effects. In presence of nonlinearity and/or variability in bioavailability, model-based phenotype allowed a higher probability to detect the SNPs than other phenotypes. In a realistic setting with a limited number of subjects, all methods showed a low ability to detect genetic effects. Ridge regression had the best probability to detect SNPs, but also a higher number of false positives. No association test showed a much higher power than the others.

Therapeutic D2/3 receptor occupancies and response with low amisulpride blood concentrations in very late-onset schizophrenia-like psychosis (VLOSLP)

Antipsychotic drug sensitivity in very late‐onset schizophrenia‐like psychosis (VLOSLP) is well documented, but poorly understood. This study aimed to investigate blood drug concentration, D2/3 receptor occupancy and outcome in VLOSLP during open amisulpride prescribing, and compare this with Alzheimers disease (AD).

A Population Approach to Guide Amisulpride Dose Adjustments in Older Patients With Alzheimer's Disease

OBJECTIVE We have previously reported high dopamine D2/3 receptor occupancies at low amisulpride concentrations in older people with Alzheimers disease (AD), during off-label treatment of AD-related psychosis. This post hoc analysis explored pharmacokinetic (concentration) and pharmacodynamic (prolactin, D2/3 occupancy) contributions to symptom reduction and extrapyramidal side effects (EPS) to inform AD-specific dose adjustments. METHODS Population pharmacokinetic-pharmacodynamic models were developed by combining pharmacokinetic data from a phase 1 study in 20 healthy older people with pharmacokinetic prolactin, [¹⁸F]fallypride D2/3 receptor imaging, and clinical outcome data from 28 older patients prescribed open amisulpride (25-75 mg/d) to treat AD-related psychosis. Model predictions were used to simulate dose-response and dose-EPS. RESULTS Symptom reduction (delusions) was associated with amisulpride concentration (P = 1.3e-05) and D2/3 occupancy (P < .01, caudate, putamen, thalamus). Model predictions suggested that across concentrations of 40-100 ng/mL, and occupancies of 40% to 70% in the caudate and thalamus and 30% to 60% in the putamen, there was a 50% to 90% probability of response and < 30% probability of EPS. Simulations, based on concentration-delusions and concentration-EPS model outputs, showed that 50 mg/d of amisulpride was the appropriate dose to achieve this target range in those aged > 75 years; increasing the dose to 75 mg/d increased the risk of EPS, particularly in those aged > 85 years of low body weight. CONCLUSIONS These findings argue strongly for the consideration of age- and weight-based dose adjustments in older patients with AD-related psychosis and indicate that 50 mg/d of amisulpride may be both the minimal clinically effective dose and, in those aged > 75 years, the maximally tolerated dose.

Combined Analysis of Phase I and Phase II Data to Enhance the Power of Pharmacogenetic Tests

We show through a simulation study how the joint analysis of data from phase I and phase II studies enhances the power of pharmacogenetic tests in pharmacokinetic (PK) studies. PK profiles were simulated under different designs along with 176 genetic markers. The null scenarios assumed no genetic effect, while under the alternative scenarios, drug clearance was associated with six genetic markers randomly sampled in each simulated dataset. We compared penalized regression Lasso and stepwise procedures to detect the associations between empirical Bayes estimates of clearance, estimated by nonlinear mixed effects models, and genetic variants. Combining data from phase I and phase II studies, even if sparse, increases the power to identify the associations between genetics and PK due to the larger sample size. Design optimization brings a further improvement, and we highlight a direct relationship between η‐shrinkage and loss of genetic signal.

IMPACT OF PSYCHOSIS SUBTYPES ON DISEASE PROGRESSION IN ALZHEIMER’S DISEASE: NONLINEAR MIXED EFFECT (NLME) MODELLING OF ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE (ADNI2) DATA

per cent of people aged over 65 haveMCI and even though it is not a type of dementia, a person with MCI is more likely to develop it. In 1999 Petersen et al. developed the criteria for distinguishing subjects with MCI from healthy controls and Alzheimer’s disease (AD) patients by comparing demographic factors and measures of cognitive function. The subjects in the study were found to have memory impairment beyond that expected for age and education, yet they were not demented. Since Petersen’s publication over 10,000 studies have been published about MCI with 250 publications describing biomarkers of MCI. We have reviewed all the publications in order to critically probe the rigor and validity of MCI biomarkers, in particular, in relation to AD. Methods: Using the keyword MCI in Pubmed all publications from 1999 until the end of 2016 were collected. Only studies with secondary data of plasma and CSF biomarkers, neuroimaging including volumetry, MRI, fMRI, SPECT, DTI, Amyloid, tau imaging and pathology were included. Results:Almost 1300 papers were printed and reviewed in detail. Over 500 papers met the inclusion criteria, for which detailed data were collected for statistical analysis and were included in the meta-analysis. In brief, over 150 publications describing CSF biomarkers, 270 papers with neuroimaging data and over 20 Pathology were included. Importantly, all the data were also parsed, whenever possible, for amnesitc versus non amnestic, uni versus multimodal MCI, converters and non converters, all split for Apo E genotype whenever possible. Conclusions:In this large, if not the largest, meta-analysis on MCI biomarkers to date we have identified strong correlation between most frequently examined CSF and imaging biomarkers, namely Ab, tau, ptau and volumetry. Interestingly, meta-analysis discloses several novel findings regarding association between some less studied biomarkers.