Individual Drug Exposure Research Articles

Recent Trends in Nanomaterial Based Electrochemical Sensors for Drug Detection: Considering Green Assessment.

An individual's therapeutic drug exposure level is directly linked to corresponding clinical effects. Rapid, sensitive, inexpensive, portable and reliable devices are needed for diagnosis related to drug exposure, treatment, and prognosis of diseases. Electrochemical sensors are useful for drug monitoring due to their high sensitivity and fast response time. Also, they can be combined with portable signal read-out devices for point-of-care applications. In recent years, nanomaterials such as carbon-based, carbon-metal nanocomposites, noble nanomaterials have been widely used to modify electrode surfaces due to their outstanding features including catalytic abilities, conductivity, chemical stability, biocompatibility for development of electrochemical sensors. This review paper presents the most recent advances about nanomaterials-based electrochemical sensors including the use of green assessment approach for detection of drugs including anticancer, antiviral, anti-inflammatory, and antibiotics covering the period from 2019 to 2023. The sensor characteristics such as analyte interactions, fabrication, sensitivity, and selectivity are also discussed. In addition, the current challenges and potential future directions of the field are highlighted.

Tumor growth inhibition modeling in patients with second line biliary tract cancer and first line non-small cell lung cancer based on bintrafusp alfa trials.

This analysis aimed to quantify tumor dynamics in patients receiving either bintrafusp alfa (BA) or pembrolizumab, by population pharmacokinetic (PK)-pharmacodynamic modeling, and investigate clinical and molecular covariates describing the variability in tumor dynamics by pharmacometric and machine-learning (ML) approaches. Data originated from two clinical trials in patients with biliary tract cancer (BTC; NCT03833661) receiving BA and non-small cell lung cancer (NSCLC; NCT03631706) receiving BA or pembrolizumab. Individual drug exposure was estimated from previously developed population PK models. Population tumor dynamics models were developed for each drug-indication combination, and covariate evaluations performed using nonlinear mixed-effects modeling (NLME) and ML (elastic net and random forest models) approaches. The three tumor dynamics' model structures all included linear tumor growth components and exponential tumor shrinkage. The final BTC model included the effect of drug exposure (area under the curve) and several covariates (demographics, disease-related, and genetic mutations). Drug exposure was not significant in either of the NSCLC models, which included two, disease-related, covariates in the BA arm, and none in the pembrolizumab arm. The covariates identified by univariable NLME and ML highly overlapped in BTC but showed less agreement in NSCLC analyses. Hyperprogression could be identified by higher tumor growth and lower tumor kill rates and could not be related to BA exposure. Tumor size over time was quantitatively characterized in two tumor types and under two treatments. Factors potentially related to tumor dynamics were assessed using NLME and ML approaches; however, their net impact on tumor size was considered as not clinically relevant.

Genetic and physiological factors predisposing to individual selective serotonine reuptake inhibitors exposure during pregnancy and breast feeding

Anxiety and depression are very common during pregnancy. Post-partum period may frequently be complicated by more pro found depression due to hormonal changes, which may lead to fatal consequences for both — the mother and the child. The most commonly prescribed group of drugs for ambulatory patient care is the group of selective serotonine reuptake inhibitors (SSRIs). Absence of clinical trials where pregnant or breast-feeding women were among the participants has led to the situation when we can rule out effectiveness and safety of this drug class for pregnant and breastfeeding women based only on real-life studies. Current know ledge let us conclude that all individual group representatives have comparable efficacy and safety profile. The choice of a single agent to use may be difficult. In our paper we analyzed genetic and non-genetic factors, that may be important for individual pharmacokinetics of various SSRIs in order to reveal the most relevant for each group representative, and to determine those drugs with the most stable pharmacokinetic parameters in pregnancy. We also tried to define the drugs that may theoretically be more clinically reliable and safe for the fetus and the newborn. We considered such factors as expected changes in drug concentration during various periods in pregnancy, probable impact of pre-existing pharmacogenetic factors of individual drug exposure, potential for drug-drug interactions, and current knowledge about the extent of drug distribution in the blood of the newborns during breastfeeding

Cyclophosphamide exposure assessed with the biomarker phosphoramide mustard-hemoglobin in breast cancer patients: The TailorDose I study

Cyclophosphamide (CPA) dosing by body surface area (BSA, m2) has been questioned as a predictor for individual drug exposure. This study investigated phosphoramide mustard-hemoglobin (PAM-Hb, pmol g−1 Hb) as a biomarker of CPA exposure in 135 female breast cancer patients receiving CPA during three courses based on BSA: 500 mg/m2 (C500 group, n = 67) or 600 mg/m2 (C600 group, n = 68). The inter-individual difference was calculated for both groups by dividing the highest through the lowest PAM-Hb value of each course. The inter-occasion difference was calculated in percentage for each individual by dividing their PAM-Hb value through the group mean per course, and subsequently dividing this ratio of the latter through the previous course. A multivariable linear regression (MLR) was performed to identify factors that explained the variation of PAM-Hb. During the three courses, the inter-individual difference changed from 3.5 to 2.1 and the inter-occasion difference ranged between 13.3% and 11.9% in the C500 group. In the C600 group, the inter-individual difference changed from 2.7 to 2.9 and the inter-occasion difference ranged between 14.1% and 11.7%. The MLR including BSA, age, GFR, and albumin explained 17.1% of the variation of PAM-Hb and was significantly better then the model including only BSA. These factors should be considered when calculating the first dose of CPA for breast cancer patients.

Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake.

AimRegorafenib is an oral multikinase inhibitor with clinical efficacy in a range of advanced solid tumours. A population pharmacokinetic (PK) model was developed to evaluate the variability of the PK of regorafenib and its pharmacologically active metabolites M‐2 and M‐5 in solid tumours.MethodsThe model was initially developed using densely sampled phase 1 data and information on food intake to incorporate enterohepatic circulation (EHC) that was identified to considerably contribute to the PK of regorafenib. This was then applied to sparsely sampled data from four phase 3 studies in patients with advanced solid tumours. The need for exact food intake data to estimate individual drug exposure was evaluated.ResultsBy incorporating EHC, the model adequately described the PK profiles of regorafenib, M‐2 and M‐5 after single and multiple doses in patients from phase 1 studies. Individual exposure in phase 3 studies was adequately described based on assumptions on the time and frequency of food intake, although exact food intake data are recommended to improve the estimation. Covariate analysis identified sex and body mass index (BMI) as impacting exposure to regorafenib, and sex as strongly impacting exposure to M‐2 and M‐5 (also influenced by the BMI effect on parent regorafenib in the joint model developed); however, these factors accounted for a small portion of the overall variability in exposure.ConclusionsThe adequate description of regorafenib PK after multiple dosing requires the incorporation of EHC. Neither single nor combined covariates predicted exposures that would warrant a priori regorafenib dose adjustment.

Gene expression responses to anti-tuberculous drugs in a whole blood model

BackgroundThere is a need for better tools to evaluate new or repurposed TB drugs. The whole blood bactericidal activity (WBA) assay has been advocated for this purpose. We investigated whether transcriptional responses in the WBA assay resemble TB responses in vivo, and whether the approach might additionally reveal mechanisms of action.Results1422 of 1798 (79%) of differentially expressed genes in WBA incubated with the standard combination of rifampicin, isoniazid, pyrazinamide and ethambutol were also expressed in sputum (P < 0.0001) obtained from patients taking the same combination of drugs; these comprised well-established treatment-response genes. Gene expression profiles in WBA incubated with the standard drugs individually, or with moxifloxacin or faropenem (with amoxicillin and clavulanic acid) clustered by individual drug exposure. Distinct pathways were detected for individual drugs, although only with isoniazid did these relate to known mechanisms of drug action.ConclusionsSubstantial agreement between whole blood cultures and sputum and the ability to differentiate individual drugs suggest that transcriptomics may add value to the whole blood assay for evaluating new TB drugs.

BET inhibitor bromosporine enhances 5-FU effect in colorectal cancer cells

Treatment of colorectal cancer (CRC) remains a challenge because of the lack of effective early treatment strategies and high incidence of relapse. 5-Fluorouracil (5-FU) is a typical CRC treatment. Bromosporine is an innovative bromodomain and extraterminal domain (BET) inhibitor. We investigated if CRC could be targeted by the combination of 5-FU and bromosporine in a synergistic manner in vivo and in vitro. Our findings shown that the combination treatment inhibits cell viability, formation of colonies, increased apoptosis and cell cycle arrest at G0-G1. In addition, the expression level of BRD4 was high in HCT116 cells exposed to 5-FU that showed lower apoptosis against the parental cells. Moreover, the 5-FU-resistance was reversed significantly by BRD4 knockdown or inhibition. The drug combination showed increased activity against tumor than individual drug exposure in the xenograft model. In conclusion, this work serves as a basic clinical evaluation of 5-FU and bromosporine as an effective therapeutic approach for CRC.

Towards Personalized Antithrombotic Treatments: Focus on P2Y12 Inhibitors and Direct Oral Anticoagulants.

Oral anticoagulants and antiplatelet drugs are commonly prescribed to lower the risk of cardiovascular diseases, such as venous and arterial thrombosis, which represent the leading causes of mortality worldwide. A significant percentage of patients taking antithrombotics will nevertheless experience bleeding or recurrent ischemic events, and this represents a major public health issue. Cardiovascular medicine is now questioning the one-size-fits-all policy, and more personalized approaches are increasingly being considered. However, the available tools are currently limited and they are only moderately able to predict clinical events or have a significant impact on clinical outcomes. Predicting concentrations of antithrombotics in blood could be an effective means of personalization as they have been associated with bleeding and recurrent ischemia. Target concentration interventions could take advantage of physiologically based pharmacokinetic (PBPK) and population-based pharmacokinetic (POPPK) models, which are increasingly used in clinical settings and have attracted the interest of governmental regulatory agencies, to propose dosages adapted to specific population characteristics. These models have the benefit of combining parameters from different sources, such as experimental in vitro data and patients' demographic, genetic, and physiological in vivo data, to characterize the dose-concentration relationships of compounds of interest. As such, they can be used to predict individual drug exposure. In the near future, these models could therefore be a valuable means of predicting personalized antithrombotic blood concentrations and, hopefully, of preventing clinical non-response or bleeding in a given patient. Existing approaches for personalization of antithrombotic prescriptions will be reviewed using practical examples for P2Y12 inhibitors and direct oral anticoagulants. The review will additionally focus on the existing PBPK and POPPK models for these two categories of drugs. Lastly, we address potential scenarios for their implementation in clinics, along with the main limitations and challenges.

Personalized Nutrition: Translating the Science of NutriGenomics Into Practice: Proceedings From the 2018 American College of Nutrition Meeting

Adverse reactions to foods and adverse drug reactions are inherent in product defects, medication errors, and differences in individual drug exposure. Pharmacogenetics is the study of genetic causes of individual variations in drug response and pharmacogenomics more broadly involves genome-wide analysis of the genetic determinants of drug efficacy and toxicity. The similarity of nutritional genomics and pharmacogenomics stems from the innate goal to identify genetic variants associated with metabolism and disease. Thus, nutrigenomics can be thought of as encompassing gene–diet interactions involving diverse compounds that are present in even the simplest foods. The advances in the knowledge base of the complex interactions among genotype, diet, lifestyle, and environment is the cornerstone that continues to elicit changes in current medical practice to ultimately yield personalized nutrition recommendations for health and risk assessment. This information could be used to understand how foods and dietary supplements uniquely affect the health of individuals and, hence, wellness. The individual’s gut microbiota is not only paramount but pivotal in embracing the multiple-functional relationships with complex metabolic mechanisms involved in maintaining cellular homeostasis. The genetic revolution has ushered in an exciting era, one in which many new opportunities are expected for nutrition professionals with expertise in nutritional genomics. The American College of Nutrition’s conference focused on “Personalized Nutrition: Translating the Science of NutriGenomics Into Practice” was designed to help to provide the education needed for the professional engagement of providers in the personalized medicine era.

Combinations of QTc-prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature.

Background:Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions.Methods:In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses.Results:Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and co-administration of a ‘known’ risk drug as a further risk factor.Conclusions:These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs.

How can we define and analyse drug exposure more precisely to improve the prediction of hospitalizations in longitudinal (claims) data?

Risk prediction models can be powerful tools to support clinical decision-making, to help targeting interventions, and, thus, to improve clinical and economic outcomes, provided that model performance is good and sensitivity and specificity are well balanced. Drug utilization as a potential risk factor for unplanned hospitalizations has recently emerged as a meaningful predictor variable in such models. Drug treatment is a rather unstable (i.e. time-dependent) phenomenon and most drug-induced events are concentration-dependent and therefore individual drug exposure will likely modulate the risk. This especially applies to longitudinal monitoring of appropriate drug treatment within claims data as another promising application for prediction models. To guide future research towards this direction, we firstly reviewed current risk prediction models for unplanned hospitalizations that explicitly included information on drug utilization and were surprised to find that these models rarely attempted to consider dose and frequent modulators of drug clearance such as interactions with co-medication or co-morbidities. As another example, they often presumed class effects where in fact, differences between active moieties were well established. In addition, the study designs and statistical risk analysis disregarded the fact that medication and risk modulators and, thus, adverse events can vary over time. In a simulation study, we therefore evaluated the potential benefit of time-dependent Cox models over standard binary regression approaches with a fixed follow-up period. Longitudinal drug information could be utilized much more efficiently both by precisely estimating individual drug exposure and by applying more refined statistical methodology to account for time-dependent drug utilization patterns.

Negative reinforcement via motivational withdrawal is the driving force behind the transition to addiction.

Piazza and Deroche-Gamonet have significantly contributed to the field of addiction and published several pioneering articles that have had a major influence on the field. The latest article by Piazza and Deroche-Gamonet is a position paper, in which they argue that they provide a foundation for the first general theory of the transition to addiction. Their theory is composed of the following three principles: (1) The transition to addiction depends on an interaction between individual vulnerability and drug exposure. (2) The transition to addiction involves at least three steps (i.e., recreational/sporadic drug use, intensified/sustained/escalated drug use, and loss of control/full addiction). (3) Addiction is a true psychiatric disease. Piazza and Deroche-Gamonet propose to test their “first” general theory of addiction by providing three predictionsthatcanbeusedtovalidateorinvalidatetheir theory.The review by Piazza and Deroche-Gamonet represents an excellent opportunity to discuss critical aspects of the transition to addiction. In this article, we attempt to test point by point the validity of their statements based on the current state of the field,withthehopethatabetterunderstandingoftheaddiction process will lead to better treatments for drug addiction. To test the validity of their claims, as suggested by Piazza and Deroche-Gamonet, it is important to define the criteria that need to be fulfilled for a novel theory to be valid. A scientific theory is a well-substantiated explanation of a phenomenon based on knowledge that has been repeatedly confirmed through observation and experimentation. Its strength is related to the diversity of phenomena it can explain and the accuracy in predicting outcomes. A scientific theory should allow for falsifiable predictions. Finally, a new theory should better explain experimental observations than previous theories and result in further testable predictions that can be confirmed. We will review each principle proposed by Piazza and Deroche-Gamonet based on each of these criteria.

Transaminase [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] Activity of HIV and HBV Co-Infected Female Patients on Drugs and Female Patients Not on Drugs

Human immunodeficiency virus-1 (HIV) and hepatitis B virus (HBV) co-infection is a major threat, especially to liver damage. 100 female patients referred to Virology department of the Jos University teaching Hospital (JUTH), were selected by physicians on the basis of the following criteria: documented HIV infection, no alcohol abuse (≤ 20 g alcohol daily and no history of chronic alcohol consumption), no history of hereditary and autoimmune liver disease, no evidence of hemochromatosis. Data on demographics, drug or alcohol use, and history of liver diseases were obtained at first visit. A month-by-month documentation of the prescribed drug combination allowed a calculation of each patient's individual cumulative drug exposure. Subjects were then classified into control (30), co-infected; on drugs (35) and co-infected; not on drugs (35). The test for HIV antibodies, HBsAg were carried out on day one (at first visit) serum ALT and serum AST were determined three (3) months after detection (day 90; after HIV antigen confirmatory test). Thirty-five (35) patients started medication at day-one, and 35 decided not to start medication until after confirmatory test (three months later).The serum ALT levels of the HIV-HBV co-infected patients on drugs (M=43.60, SD=1.83) was significantly higher than the serum ALT levels of the control group (M=29.17, SD=6.17), t (63) =12, p< .0001 at p <.05 confidence level. In a similar trend, the serum ALT levels of the HIV-HBV co-infected patients not on drugs (M=37.74, SD=3.70) was significantly higher than the serum ALT levels of the control group (M=29.17, SD=6.17), t (63) =6.5, p< .0001 at p <.05 confidence level. On comparison, the serum ALT levels of the HIV- HBV co-infected patients on drugs (M=43.60, SD=1.83) was significantly higher than the serum ALT levels of the HIV-HBV co-infected patients not on drugs (M=37.74, SD=3.70), t (68) =8.40, p< .0001 at p <.05 confidence level. The serum AST levels of the HIV-HBV co-infected patients on drugs (M=43.54, SD=2.74) was significantly higher than the serum AST levels of the control group (M=32.23, SD=5.93), t (63) =10, p< .0001 at p <.05 confidence level. In a similar manner, the serum AST levels of the HIV-HBV co-infected patients not on drugs (M=37.66, SD=2.11) was significantly higher than the serum AST levels of the control group (M=32.23, SD=5.93), t (63) =5.1, p< .0001 at p <.05 confidence level. On comparison, the serum AST levels of the HIV-HBV co-infected patients on drugs (M=43.54, SD=2.74) was significantly higher than the serum AST levels of the HIV-HBV co-infected patients not on drugs (M=37.66, SD=2.11), t (68) =10.07, p< .0001 at p <.05 confidence level. HIV-HBV infection causes liver damage with more damage caused by drugs taken to manage these infections. A correlation analysis between ALT and AST levels shows a non-significant correlation.

Transaminase [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] Activity of HIVFemale Patients on Drugs and Female Patients Not on Drugs

Elevated serum transaminase (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) levels have been reported in human immunodeficiency virus (HIV)-infected patients on combination antiretroviral therapy (cART). 100 female patients referred to Virology department of the Jos University teaching Hospital (JUTH), were randomly selected by their physicians on the basis of the following criteria: documented HIV infection, no alcohol abuse (≤ 20 g alcohol daily and no history of chronic alcohol consumption), no history of hereditary and autoimmune liver disease, no evidence of hemochromatosis. Patients with any contraindication for liver biopsy were excluded. Data on demographics, drug or alcohol use, and history of liver diseases were obtained at first visit. Subjects were then classified into control (30), HIV-infected; not on drugs (35) HIV-infected; on drugs (35);a month-by-month documentation of the prescribed drug combination for patients who started medication, provided an avenue for calculating each patient's individual cumulative drug exposure. The test for HIV antibodies, HBsAg were carried out on day one (at first visit) serum ALT and serum AST were determined three (3) months after detection (day 90; after HIV antigen confirmatory test). Thirty-five (35) patients started medication at day one and 35 decided not to start medication until after confirmatory test (three months later).The serum ALT levels of the HIV infected patients on drugs (M=43.94, SD=4.30) was significantly higher than the serum ALT levels of the control group (M=29.17, SD=6.17), t (63) = 10.72, p < .0001 at p <.005 confidence level. In a similar trend, the serum ALT levels of the HIV infected patients not on drugs (M=41.17, SD=2.06) was significantly higher than the serum ALT levels of the control group (M=29.17, SD=6.17), t (63) =10.05, p < .0001 at p <.005 confidence level. On comparison, the serum ALT levels of the HIV infected patients on drugs (M=43.94, SD=4.30) was significantly higher than the serum ALT levels of the HIV infected patients not on drugs (M=41.17, SD=2.06), t (68) = 3.44, p < .0001 at p <.005 confidence level. The serum AST levels of the HIV infected patients on drugs (M=44.54, SD=4.85) was significantly higher than the serum AST levels of the control group (M=32.23, SD=5.93), t (63) =9.21, p < .0001 at p <.005 confidence level. In a similar manner, the serum AST levels of the HIV infected patients not on drugs (M=39.91, SD=1.67) was significantly higher than the serum AST levels of the control group (M=32.23, SD=5.93), t (63) =7.33, p < .0001 at p <.005 confidence level. On comparison, the serum AST levels of the HIV infected patients on drugs (M=44.54, SD=4.85) was significantly higher than the serum AST levels of the HIV infected patients not on drugs (M=39.91, SD=1.67), t (68) = 5.34, p < .0001 at p <.005 confidence level.A correlation plot between ALT and AST levels showed a non-significant correlation between these transaminases in the three groups. Control group (r = 0.098, p < 0.05), HIV (+ve), and HBV (-ve) patients on drugs (r = -0.038, p < 0.05), HIV (+ve), and HBV (-ve) patients not on drugs (r = 0.201, p < 0.05).It has been observed from the study that a significant elevation of liver transaminase levels (ALT and AST) is a serious risk factor associated with management of HIV management with drugs.

A model-based approach to analyze the influence of UGT2B15 polymorphism driven pharmacokinetic differences on the pharmacodynamic response of the PPAR agonist sipoglitazar

The pharmacokinetics of sipoglitazar, a peroxisome proliferator activated receptor agonist, are subject to high inter-individual variability resulting from a polymorphism of the UGT2B15 genotype. The aim of the current analysis was to apply a PK-PD model-based approach to evaluate the influence of UGT2B15 driven pharmacokinetic differences on the clinical response. Efficacy and safety of sipoglitazar compared to placebo were assessed in Type 2 Diabetes Mellitus patients in two Phase II randomized, double-blind studies (sipoglitazar once daily: 8, 16, 32, or 64 mg; sipoglitazar twice daily: 16 or 32 mg; rosiglitazone 8 mg once daily and placebo for 13 weeks; n = 780). Changes in fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1c) levels over time were described as a function of individual drug exposure using a simultaneous, cascading indirect response model structure. The effects on FPG and HbA1c could successfully be described for placebo, rosiglitazone, and sipoglitazar treated groups in all three UGT2B15 genotypes. Differences in drug effects between genotypes were fully explained by differences in drug exposure. The current PK-PD analysis confirms that UGT2B15 genotype is a major determinant for differences in FPG and HbA1c response to sipoglitazar treatment between Type 2 Diabetes mellitus patients, due to related differences in drug exposure.

Challenging Recommended Oral and Intravenous Voriconazole Doses for Improved Efficacy and Safety: Population Pharmacokinetics–Based Analysis of Adult Patients With Invasive Fungal Infections

Recommended oral voriconazole (VRC) doses are lower than intravenous doses. Because plasma concentrations impact efficacy and safety of therapy, optimizing individual drug exposure may improve these outcomes. A population pharmacokinetic analysis (NONMEM) was performed on 505 plasma concentration measurements involving 55 patients with invasive mycoses who received recommended VRC doses. A 1-compartment model with first-order absorption and elimination best fitted the data. VRC clearance was 5.2 L/h, the volume of distribution was 92 L, the absorption rate constant was 1.1 hour(-1), and oral bioavailability was 0.63. Severe cholestasis decreased VRC elimination by 52%. A large interpatient variability was observed on clearance (coefficient of variation [CV], 40%) and bioavailability (CV 84%), and an interoccasion variability was observed on bioavailability (CV, 93%). Lack of response to therapy occurred in 12 of 55 patients (22%), and grade 3 neurotoxicity occurred in 5 of 55 patients (9%). A logistic multivariate regression analysis revealed an independent association between VRC trough concentrations and probability of response or neurotoxicity by identifying a therapeutic range of 1.5 mg/L (>85% probability of response) to 4.5 mg/L (<15% probability of neurotoxicity). Population-based simulations with the recommended 200 mg oral or 300 mg intravenous twice-daily regimens predicted probabilities of 49% and 87%, respectively, for achievement of 1.5 mg/L and of 8% and 37%, respectively, for achievement of 4.5 mg/L. With 300-400 mg twice-daily oral doses and 200-300 mg twice-daily intravenous doses, the predicted probabilities of achieving the lower target concentration were 68%-78% for the oral regimen and 70%-87% for the intravenous regimen, and the predicted probabilities of achieving the upper target concentration were 19%-29% for the oral regimen and 18%-37% for the intravenous regimen. Higher oral than intravenous VRC doses, followed by individualized adjustments based on measured plasma concentrations, improve achievement of the therapeutic target that maximizes the probability of therapeutic response and minimizes the probability of neurotoxicity. These findings challenge dose recommendations for VRC.

A study of toxicity and differential gene expression in murine liver following exposure to anti-malarial drugs: amodiaquine and sulphadoxine-pyrimethamine

BackgroundAmodiaquine (AQ) along with sulphadoxine-pyrimethamine (SP) offers effective and cheaper treatment against chloroquine-resistant falciparum malaria in many parts of sub-Saharan Africa. Considering the previous history of hepatitis, agranulocytosis and neutrocytopenia associated with AQ monotherapy, it becomes imperative to study the toxicity of co-administration of AQ and SP. In this study, toxicity and resulting global differential gene expression was analyzed following exposure to these drugs in experimental Swiss mice.MethodsThe conventional markers of toxicity in serum, oxidative stress parameters in tissue homogenates, histology of liver and alterations in global transcriptomic expression were evaluated to study the toxic effects of AQ and SP in isolation and in combination.ResultsThe combination therapy of AQ and SP results in more pronounced hepatotoxicity as revealed by elevated level of serum ALT, AST with respect to their individual drug exposure regimen. Furthermore, alterations in the activity of major antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase, glutathione reductase), indicating the development of oxidative stress, was more significant in AQ+SP combination therapy. cDNA microarray results too showed considerably more perturbed gene expression following combination therapy of AQ and SP as compared to their individual drug treatment. Moreover, a set of genes were identified whose expression pattern can be further investigated for identifying a good biomarker for potential anti-malarial hepatotoxicity.ConclusionThese observations clearly indicate AQ+SP combination therapy is hepatotoxic in experimental Swiss mice. Microarray results provide a considerable number of potential biomarkers of anti-malarial drug toxicity. These findings hence will be useful for future drug toxicity studies, albeit implications of this study in clinical conditions need to be monitored with cautions.

Positive and Negative drug Selection Pressures on the N348I Connection Domain Mutation: New Insights from in vivo Data

There is conflicting evidence on specific reverse transcriptase inhibitors to which the N348I mutation in the connection domain of HIV type-1 reverse transcriptase confers resistance. Here, we examined associations between the emergence of N348I and antiretroviral history in a large clinical database. We analysed 5,353 resistance tests (that were sequenced beyond codon 348) among 2,266 antiretroviral-experienced patients. Associations between N348I and individual antiretroviral drug exposure were estimated using a matched case-control approach. Cases were defined as the first resistance test where N348I was detected; for each case, the 10 closest (in calendar time) N348N tests were selected as controls. Odds ratios (ORs) adjusted for effects of all other drugs were estimated by conditional logistic regression. N348I was detected in 198 (8.7%) cases. Drugs that were statistically significantly positively associated with N348I were efavirenz (OR 1.55, 95% confidence interval [CI] 1.08-2.23; P=0.017) and nevirapine (OR 2.06, 95% CI 1.49-2.85; P<0.001). Tenofovir disoproxil fumarate (TDF) was significantly negatively associated (OR 0.27, 95% CI 0.15-0.48; P<0.001) with N348I. Similar findings were observed when the analysis was repeated to include only those tests within 2 years of the resistance test. Effects for zidovudine and stavudine were evident only in an additional analysis, which considered exposure to both drugs jointly within 2 years prior to the resistance test: exposure to zidovudine alone (OR 4.61, 95% CI 1.83-11.61; P<0.001) and exposure to stavudine alone (OR 3.39, 95% CI 1.32-8.71; P=0.011). This is the first clinical evidence to suggest that efavirenz might select for N348I in addition to nevirapine, that stavudine might select for N348I in addition to zidovudine and that TDF might protect against the mutation.

Effect of human immunodeficiency virus type 1 protease inhibitor therapy and subtype on development of resistance in subtypes B and G

Europe is currently observing a significant rise in non-B subtypes. Consequently, the effect of genetic variability on therapy response or genotypic resistance interpretation algorithms is an emerging concern. The purpose of this study is to investigate the amino acid substitutions selected under drug pressure in the protease of human immunodeficiency virus type 1 (HIV-1) subtypes B and G, and determine if there are any significant differences. We investigated therapy-related and subtype-related substitutions in the protease, considering subtype, overall protease inhibitor treatment and individual drug exposure. Many mutations were significantly related to protease inhibitor (PI) therapy, with mutations exclusive to subtype B or subtype G. Some mutations are at positions related to resistance in both subtypes, but the amino acid substitution is different. Other mutations were significantly associated with subtype and PI selective pressure ( p < 0.05), pointing towards a differential selective pressure in both subtypes. We confirmed previous reports on the subtype-dependent selection of D30N and 89I, and identified a new mutation with such differential selective pressure: 37D was preferentially selected by lopinavir in subtype B. Other novel mutations found under therapy pressure were 13A, 35N, K55R, I66F, I72L/T, T74S, 82M and 89I/V. Our study indicates that even though in general, drug selective pressure and resistance pathways are relatively similar between subtypes B and G, some differences do occur, leading to subtype-dependent substitutions.

PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid ω‐Hydroxylase (CYP4) Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease

Fatty liver disease is a common lipid metabolism disorder influenced by the combination of individual genetic makeup, drug exposure, and life-style choices that are frequently associated with metabolic syndrome, which encompasses obesity, dyslipidemia, hypertension, hypertriglyceridemia, and insulin resistant diabetes. Common to obesity related dyslipidemia is the excessive storage of hepatic fatty acids (steatosis), due to a decrease in mitochondria β-oxidation with an increase in both peroxisomal β-oxidation, and microsomal ω-oxidation of fatty acids through peroxisome proliferator activated receptors (PPARs). How steatosis increases PPARα activated gene expression of fatty acid transport proteins, peroxisomal and mitochondrial fatty acid β-oxidation and ω-oxidation of fatty acids genes regardless of whether dietary fatty acids are polyunsaturated (PUFA), monounsaturated (MUFA), or saturated (SFA) may be determined by the interplay of PPARs and HNF4α with the fatty acid transport proteins L-FABP and ACBP. In hepatic steatosis and steatohepatitis, the ω-oxidation cytochrome P450 CYP4A gene expression is increased even with reduced hepatic levels of PPARα. Although numerous studies have suggested the role ethanol-inducible CYP2E1 in contributing to increased oxidative stress, Cyp2e1-null mice still develop steatohepatitis with a dramatic increase in CYP4A gene expression. This strongly implies that CYP4A fatty acid ω-hydroxylase P450s may play an important role in the development of steatohepatitis. In this review and tutorial, we briefly describe how fatty acids are partitioned by fatty acid transport proteins to either anabolic or catabolic pathways regulated by PPARs, and we explore how medium-chain fatty acid (MCFA) CYP4A and long-chain fatty acid (LCFA) CYP4F ω-hydroxylase genes are regulated in fatty liver. We finally propose a hypothesis that increased CYP4A expression with a decrease in CYP4F genes may promote the progression of steatosis to steatohepatitis.