Sources Of Pharmacokinetic Variability Research Articles

Integrated multiple analytes and semi-mechanistic population pharmacokinetic model of tusamitamab ravtansine, a DM4 anti-CEACAM5 antibody-drug conjugate

Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate (ADC), combining a humanized monoclonal antibody (IgG1) targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and a potent cytotoxic maytansinoid derivative, DM4, inhibiting microtubule assembly. SAR408701 is currently in clinical development for the treatment of advanced solid tumors expressing CEACAM5. It is administered intravenously as a conjugated antibody with an average Drug Antibody Ratio (DAR) of 3.8. During SAR408701 clinical development, four entities were measured in plasma: conjugated antibody (SAR408701), naked antibody (NAB), DM4 and its methylated metabolite (MeDM4), both being active. Average DAR and proportions of individual DAR species were also assessed in a subset of patients. An integrated and semi-mechanistic population pharmacokinetic model describing the time-course of all entities in plasma and DAR measurements has been developed. All DAR moieties were assumed to share the same drug disposition parameters, excepted for clearance which differed for DAR0 (i.e. NAB entity). The conversion of higher DAR to lower DAR resulted in a DAR-dependent ADC deconjugation and was represented as an irreversible first-order process. Each conjugated antibody was assumed to contribute to DM4 formation. All data were fitted simultaneously and the model developed was successful in describing the pharmacokinetic profile of each entity. Such a structural model could be translated to other ADCs and gives insight of mechanistic processes governing ADC disposition. This framework will further be expanded to evaluate covariates impact on SAR408701 pharmacokinetics and its derivatives, and thus can help identifying sources of pharmacokinetic variability and potential efficacy and safety pharmacokinetic drivers.

Treating children with tuberculosis—Using pharmacometrics to do better

Treating children with tuberculosis—Using pharmacometrics to do better

Inter-ethnic differences in pharmacokinetics-is there more that unites than divides?

Inter‐ethnic variability in pharmacokinetics (PK) has been attributed to several factors ranging from genetic to environmental. It is not clear how current teaching in higher education (HE) reflects what published literature suggests on this subject. This study aims to gain insights into current knowledge about inter‐ethnic differences in PK based on reports from published literature and current teaching practices in HE. A systematic literature search was conducted on PubMed and Scopus to identify suitable literature to be reviewed. Insights into inter‐ethnic differences in PK teaching among educators in HE and industry were determined using a questionnaire. Thirty‐one percent of the studies reviewed reported inter‐ethnic differences in PK, of these, 37% of authors suggested genetic polymorphism as possible explanation for the inter‐ethnic differences observed. Other factors authors proposed included diet and weight differences between ethnicities. Most respondents (80%) who taught inter‐ethnic difference in PK attributed inter‐ethnic differences to genetic polymorphism. While genetic polymorphism is one source of variability in PK, the teaching of genetic polymorphism is better associated with interindividual variabilities rather than inter‐ethnic differences in PK as there are no genes with PK implications specific to any one ethnic group. Nongenetic factors such as diet, weight, and environmental factors, should be highlighted as potential sources of interindividual variation in the PK of drugs.

Inflammation Induces Changes in the Functional Expression of P-gp, BCRP, and MRP2: An Overview of Different Models and Consequences for Drug Disposition.

The ATP-binding cassette (ABC) transporters play a key role in drug pharmacokinetics. These membrane transporters expressed within physiological barriers can be a source of pharmacokinetic variability. Changes in ABC transporter expression and functionality may consequently affect the disposition of substrate drugs, resulting in different drug exposure. Inflammation, present in several acute and chronic diseases, has been identified as a source of modulation in drug transporter expression leading to variability in drug response. Its regulation may be particularly dangerous for drugs with a narrow therapeutic index. In this context, numerous in vitro and in vivo models have shown up- or downregulation in the expression and functionality of ABC transporters under inflammatory conditions. Nevertheless, the existence of contradictory data and the lack of standardization for the models used have led to a less conclusive interpretation of these data.

Population pharmacokinetics and exposure-response relationship of trastuzumab and bevacizumab in early-stage breast cancer.

To describe the sources of interindividual variability of bevacizumab and trastuzumab pharmacokinetics in early-stage breast cancer, and to study the relationship between exposure and both early clinical response and specific adverse events. Patients (n = 86) received 6 cycles of docetaxel + trastuzumab. Early tumour response was assessed by determination of the maximum standard uptake value (SUVmax) variation (ΔSUVmax) after 1 cycle using [18F]-fluorodeoxyglucose (FDG) PET. Early poor responders (ΔSUVmax < 70%) also received bevacizumab from cycle 3 to cycle 6. Sources of interindividual variability in pharmacokinetics of both antibodies were studied by population compartment modelling. Exposure as assessed by area under the concentration-versus-time curve (AUC) was compared between responders and non-responders and between patients experiencing specific adverse events or not. A two-compartment model described the pharmacokinetics of both antibodies satisfactorily. Their central volume of distributions (Vc) increased with body surface area and their elimination half-lives were shorter (~14days) than previously reported (~26-28days). There was a time-dependent increase in trastuzumab Vc, positively correlated to baseline SUVmax. Bevacizumab elimination rate (k10) was positively correlated with ΔSUVmax measured at the end of the first cycle. Bevacizumab had no significantly influence on trastuzumab pharmacokinetics. No relationship between exposure and clinical response or occurrence of adverse events was found. Tumour uptake as assessed by SUVmax influences the pharmacokinetics of bevacizumab and trastuzumab. In early-stage breast cancer, elimination half-lives of these therapeutic monoclonal antibodies may be shorter than those previously reported in more advanced disease.

A New Approach to Measure Adherence to Medicines Using Biomarkers and Sensors.

Approximately one in two patients with a chronic disease does not take their medicines as prescribed. Poor adherence is a worldwide epidemic and a major source of variability in pharmacokinetics (PK) and pharmacodynamics. Without addressing adherence, precision medicine is unlikely to come to fruition. In drug development, poor adherence confounds the estimates for efficacy and safety of drug candidates. Accurate and high-resolution measurement of adherence is a first step toward effective interventions against poor adherence. We describe a new cross-technology platform to measure adherence. The approach involves, first, building PK models to explain dose-exposure relationships. The model incorporates PK biomarkers by genotyping or phenotyping of drug metabolism, transport and other drug clearance pathways. Importantly, dose-exposure data for model building are obtained in healthy volunteer and/or patient cohorts who are ascertained for full adherence, using edible ingestion sensors (IS) that digitize orally administered medicines. Second, the built model is harnessed to back calculate the dose actually ingested by patients, given the empirically observed drug exposure, PK biomarker, demographic, and other patient data. The proposed platform is envisioned to result in development of both drug and drug-specific companion software for adherence measurement. In terms of feasibility, the new approach overlaps with current drug development timelines spanning the Phase 1 to 4 clinical trial continuum, and thus, could conceivably be implemented without requiring significant changes to the time sensitive clinical trial processes. For the IS-powered tools, the proposed platform creates a new space for applications in clinical trials to ensure adherence.

Should Race-Genotype Interactions Be Considered in the Global Development of CYP2C19 Substrates? A Proposed Framework Using Physiologically Based Pharmacokinetic Modeling.

Should Race-Genotype Interactions Be Considered in the Global Development of CYP2C19 Substrates? A Proposed Framework Using Physiologically Based Pharmacokinetic Modeling.

Association between the CYP11 family and six cancer types.

Cytochromes P450 (CYPs) are a major source of variability in pharmacokinetics and drug response. CYPs utilize a variety of small and large molecules as substrates in enzymatic reactions. The CYP genes may be divided into two groups: Endogenous CYPs (CYP family 7–51) and xenobiotic CYPs (CYP family 1–4). The aim of the present study was to investigate whether endogenous CYPs exhibit similar gene expression and mutations in various cancer types. The gene expression profiles and somatic mutations exhibited in colon adenocarcinoma, kidney renal clear cell carcinoma, liver hepatocellular carcinoma, lung squamous cell carcinoma, prostate adenocarcinoma and uterine corpus endometrial carcinoma were analyzed using data obtained from The Cancer Genome Atlas. The expression of CYP11A1 was significantly downregulated in all six cancer types. In addition, CYP11B1 and CYP11B2 exhibited the highest number of mutations among endogenous CYPs in all samples. As the CYP11 family is important for steroid biosynthesis, and previous studies have demonstrated that steroid hormones are associated with certain cancers, these results indicate a common role of the CYP11 family in various cancer types.

Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers.

In this study, we aimed to quantify the effects of the N-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolism in vivo and identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤ Cmax ≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

Evaluation of the pharmacokinetics and clinical utility of isavuconazole for treatment of invasive fungal infections

Introduction: Invasive fungal infections remain a leading cause of infectious morbidity and mortality in immunocompromised patients. There are relatively few effective antifungal agents, and currently available agents all have significant limitations. Isavuconazole is a novel second-generation triazole with broad-spectrum antifungal activity, and a favorable pharmacokinetic–pharmacodynamic profile. Isavuconazole is available as an oral and intravenous formulation. Phase III studies that are examining the efficacy of isavuconazole for invasive candidiasis and invasive aspergillosis are currently in progress.Areas covered: This review provides a summary of the pharmacological characteristics of isavuconazole and the potential future use of this agent. The preclinical and clinical pharmacokinetics and pharmacodynamics are discussed. This review was constructed by searching isavuconazole, triazole, pharmacokinetics and pharmacodynamics in PubMed. References and abstracts that were not identified by this method were retrieved from the respective publications.Expert opinion: Isavuconazole has the potential to become an important agent for the treatment of invasive fungal infections, principally because of its relatively broad and potent in vitro antifungal activity, and its favorable pharmacokinetic profile. Further preclinical and clinical studies are required to define the clinical utility of this agent, especially for invasive candidiasis and invasive aspergillosis. Further information is required on the likely drug interactions, and in vitro susceptibility breakpoints for medically important invasive fungal pathogens. Further pharmacokinetic studies are also required in a range of patient populations to quantify the extent and sources of pharmacokinetic variability.

Assessment of Activity Levels for CYP2D6*1, CYP2D6*2, and CYP2D6*41 Genes by Population Pharmacokinetics of Dextromethorphan

The pharmacokinetics of dextromethorphan (DM) is markedly influenced by cytochrome P450 2D6 (CYP2D6) enzyme polymorphisms. The aim of this study was to quantify the effects of the CYP2D6*1, *2, and *41 variants on DM metabolism in vivo and to identify other sources of pharmacokinetic variability. Concentrations of DM and dextrorphan (DO) in plasma and urine were evaluated in 36 healthy Caucasian men. These volunteers participated in three clinical studies and received a single oral dose of 30mg DM-HBr. Data were modeled simultaneously using the population pharmacokinetics NONMEM software. A five-compartment model adequately described the data. The activity levels of the alleles assessed differed significantly. The clearance attributable to an individual CYP2D6*1 copy was 2.5-fold higher as compared with CYP2D6*2 (5,010 vs. 2,020l/h), whereas the metabolic activity of CYP2D6*41 was very low (85l/h). Urinary pH was confirmed as a significant covariate for DM renal clearance. These results refine genotype-based predictions of pharmacokinetics for DM and presumably for other CYP2D6 substrates as well.

Issues in drug metabolism of major antihypertensive drugs: β-blockers, calcium channel antagonists and angiotensin receptor blockers

Several first-line antihypertensive drugs, including calcium channel blockers, β-adrenergic blockers and angiotensin receptor blockers, undergo metabolism through different CYP isoforms. As a consequence of CYP-dependent metabolism, wide interindividual variability of plasma concentrations of antihypertensive drugs has been found in clinical practice compromising blood pressure lowering response and clinical outcomes. Several factors, including aging, hepatic impairment, drug interactions, conditions affecting hepatic blood supply and polymorphisms, contribute to changes in oral and systemic clearance affecting drug exposure during antihypertensive therapy and cardiovascular response. Considering that the degree of blood pressure reduction is related to antihypertensive drug plasma concentrations, a greater knowledge of the sources of pharmacokinetic variability of hepatically eliminated antihypertensive drugs and the applicability of an individualized approach in hypertension management by means of pharmacokinetic/pharmacodynamic modeling and pharmacogenetic testing could enhance blood pressure lowering response to pharmacological therapy. The aim of the present review is to discuss the relevance of drug metabolism in the treatment of hypertension.

Is there a therapeutic window with some antidepressants for analgesic response?

Most antidepressants and anticonvulsants used in chronic pain syndromes have dose- and concentration-response curves developed for their application to treat psychiatric disorders. Because these are important clinical tools in medication management of psychiatric syndromes, it is reasonable to expect that utilizing concentration-effect relationships and known sources of pharmacokinetic variability for determining doses for analgesia may also improve treatment tolerability and outcomes. Efforts to identify dosing "therapeutic windows" or minimum "thresholds" for analgesic efficacy have provided useful guidance for initiating treatment, reducing toxicity, and assisting with decision making in the face of limited therapeutic response. This article reviews the strengths, limitations, and potential of therapeutic drug monitoring of antidepressants and anticonvulsants as analgesics for selected chronic pain syndromes.

Utility and Application of Urine Drug Testing in Chronic Pain Management With Opioids

Important scientific principles of pain medicine pharmacology affect urine drug testing (UDT). This paper reviews sources of variability in pharmacokinetics, pharmacodynamics, pharmacogenetics, and issues relating to the collection, handling, and assay of urine and how these factors may affect test interpretation and application. Articles concerning the pharmacokinetics, pharmacodynamics, and pharmacogenetics of opioids are reviewed and interpreted for pain clinicians who treat patients with chronic opioid therapy. These data are applied to the use of UDT. Intraindividual and interindividual variability in drug metabolizing enzyme activity due to genetic polymorphisms or environmental effects can result in day-to-day and patient-to-patient variability in drug exposure. Transporters, also under genetic and environmental control, can play an important role in opioid response and contribute to the significant variability in opioid pharmacokinetics and response. The use of urine creatinine concentration to adjust urine drug concentrations, discussion of UDT assays, and application of UDT in light of an understanding of pharmacokinetics, pharmacodynamics, and pharmacogenetics are reviewed. In addition, the methodology used for testing has an important role in accuracy. Because of these factors, UDT cannot be used to determine patient compliance with a specific opioid dose. UDT, when used with an understanding of the principles of pharmacokinetics, pharmacodynamics, and pharmacogenetics of opioids, can be a useful tool in chronic pain management. Clinicians must keep in mind the limitations, purpose, and value of UDT, and the inability to predict patient compliance with a drug dosage using commercial algorithms.

A clinical trial on absorption and N‐acetylation of oral and rectal mesalazine

Mesalazine (5-ASA) is a standard treatment for ulcerative colitis. Extent of absorption and N-acetylation determine systemic exposure to 5-ASA, and are thereby relevant for the safety of the treatment. The aim of the study was to compare absorption and N-acetylation of 5-ASA following rectal or oral drug administration. Healthy subjects were compared to patients with ulcerative colitis to evaluate the impact of chronic inflammation of colorectal mucosa on disposition of 5-ASA. First, 12 healthy adults were randomized to receive 2 g of 5-ASA by each of four different formulations: oral delayed release granules, 30 mL enema, 60 mL rectal foam, and 120 mL rectal foam. Second, 12 patients with active ulcerative colitis received 60 mL rectal foam. Pharmacokinetic analysis was performed by determination of 5-ASA and its acetylated, pharmacologically inactive metabolite (Ac-5-ASA) in plasma and urine. First, systemic exposure to 5-ASA was markedly lower after rectal drug administration as compared to oral dosing (P < 0.001; e.g. median relative bioavailability of 60 mL rectal foam: 36%). Second, N-acetylation of rectal 5-ASA was lower in patients than in healthy subjects [area under the curve (AUC) ratio Ac-5-ASA/5-ASA: 1.6 +/- 0.5 vs. 2.3 +/- 0.4, mean +/- SD, P < 0.01]. High peak plasma concentrations of 5-ASA were correlated with high microscopic disease activity (r = 0.67, P < 0.05). Rectal delivery of 5-ASA results in low systemic drug exposure with potentially reduced toxicity in comparison with oral drug administration. Chronic inflammation of colorectal mucosa might be a relevant source of variability in pharmacokinetics of 5-ASA.

Pharmacogenetics of antiretroviral drugs for the treatment of HIV-infected patients: An update

Highly active antiretroviral therapy (HAART), a combination of at least three antiretroviral drugs, has dramatically improved the prognosis of HIV/AIDS. However, viral replication under therapy can lead to the selection of drug resistant viruses and subsequent virologic failure. While poor adherence is likely to be the main cause of treatment failure, individual pharmacokinetic variability can also play an important role. Drug–drug interactions, drug–food interactions, sex, age, renal/hepatic function and pregnancy are all sources of pharmacokinetic variability. Recent pharmacogenetic studies of antiretroviral drugs reported the influence of several genetic polymorphisms on antiretroviral drug exposure, toxicity and response to treatment. Initially, a single nucleotide polymorphism (SNP) in exon 26 (C3435T) of the multi-drug transporter gene (MDR1) was reported to be associated with low antiretroviral plasma drug levels but good initial immunological response; however, conflicting results have since been reported. Several studies on efavirenz, a commonly used antiretroviral drug, have reported higher plasma exposure and early side effects with the homozygous variant of the hepatic cytochrome P450 enzyme CYP2B6 G516T polymorphism, which are more frequently found in African–American subjects. However, despite its association with efavirenz exposure this polymorphism was not associated with time to virologic or toxicity-related failure. Genetic analysis has also proven to be a valuable predictor of antiretroviral drug hypersensitivity reactions; genetic screening of patients prior to initiation of specific antiretrovirals has proven to reduce the incidence of drug hypersensitivity in certain settings. The reasons for antiretroviral treatment failure are multi-factorial but as the individualization of HAART increases understanding the influence of specific genotypes on treatment success and toxicity could further optimize these life-saving treatments.

Significant Intestinal Excretion, One Source of Variability in Pharmacokinetics of COL-3, a Chemically Modified Tetracycline

This study was undertaken to examine the disposition of COL-3, a chemically modified tetracycline, in order to elucidate its major route of elimination as one possible source of the variability in pharmacokinetics of COL-3 in vivo. The disposition profile of COL-3 in vivo was assessed by examining the urinary and fecal excretion of the unchanged drug and/or its metabolites in rats after single intravenous and oral administration. The biliary excretion of COL-3 administered orally in bile duct-cannulated rats was also examined. In addition, plasma protein binding and cytochromes P450-mediated metabolism were explored along with erythrocyte partitioning in vivo. Furthermore, transport of COL-3 across Caco-2 monolayers was performed to elucidate the mechanism of intestinal excretion of COL-3 in vivo. COL-3 was extensively bound to plasma protein in rat (98%) and human plasma (95%). The affinity of rat blood cells for COL-3, as measured by the ratio of drug concentration in blood cells to that unbound in plasma, was about 36. Of the single intravenous and oral doses, less than 0.2% and 0.03% were excreted unchanged in rat urine, respectively; while 32.1 +/- 9.9% and 38.8 +/- 6.1% were recovered unchanged in rat feces, respectively, within 48 h postdosing. Of the oral dose, 1.36 +/- 0.66% and 2.97 +/- 0.88% were excreted in rat bile as the unchanged COL-3 and the total of COL-3 and its glucuronide conjugate, respectively, within 24 h after dosing. COL-3 had insignificant cytochrome P450-mediated metabolism but underwent phase II metabolism (i.e., glucuronidation) in a minor quantity. COL-3 was not a substrate of P-glycoprotein. Its transport across Caco-2 monolayers was significantly affected by protein binding and pH. Intestinal excretion, a route different from biliary excretion, is the major route of elimination for COL-3 in rats. Variability in intestinal excretion, due to extreme variable intestinal contents (food and digestive fluids), could be one source of variability in COL-3 pharmacokinetics in vivo in addition to the dissolution rate-limited absorption.

Concentration-QTC modeling in healthy volunteers (HV) and in subjects with major depressive disorder (MDD) for a novel antidepressant candidate

Purpose Evaluation of QTc vs. concentration relationship was undertaken to assess QTc prolongation early in drug development for a novel antidepressant. Objective To evaluate the QTc to concentration relationship in HV and MDD subjects at high concentrations and to predict QTc prolongation in MDD subjects for various sources of pharmacokinetic variability. Methods 28 healthy subjects and 31 subjects with MDD were studied. All subjects received 10 mg QD on Day 1 followed by 30 mg on days 2-6 of the antidepressant candidate. In addition, healthy volunteers received 60 mg QD on days 7–9. Triplicate time-matched baseline ECG data on two baseline days were collected. Triplicate and singlet ECG measurements were collected during treatment arms. Delta QTcF (Fridericia) was modeled using NONMEM v.5. Intercept vs. slope/intercept models were employed. Influence of disease state was also tested. Nonparametric bootstrap was used to construct 95% confidence intervals. Results Concentrations were similar in HV and MDD subjects. A linear QtcF vs. concentration relationship best described the data. HV and MDD subjects had similar slope estimates. Slope for HV: 0.0375 (0.0206, 0.0555) and for MDD: 0.03501 (0.0203, 0.0508). Conclusions Due to the similarity of slope in HV and MDD subjects, use of a population PK/PD model based on phase I data allows for the projection of QTcF in such cases as overdose and drug-drug interaction. Clinical Pharmacology & Therapeutics (2004) 75, P88–P88; doi: 10.1016/j.clpt.2003.11.336

Bioequivalence Parameters of Parent Drug and Its First-Pass Metabolite: Comparative Sensitivity to Sources of Pharmacokinetic Variability

The relative susceptibilities of a drug and its first-pass metabolite to various forms of pharmacokinetic variability were studied. Plasma concentrations of both species were simulated under conditions of interindividual variability in intrinsic hepatic clearance, intraindividual variability in hepatic clearance, and/or a concentration-dependent model for assay error. In comparison to the metabolite, the plasma concentrations of the parent drug displayed a heightened sensitivity to all forms of error. The bioequivalence parameters, AUC, Cmax, and Tmax of the parent drug and the metabolite were determined from an abbreviated data set. Compared to the metabolite, the AUC and Cmax of the parent drug were much more sensitive to the added variability. The Tmax of both species displayed similar variability. For a given level of manufacturer risk, a much larger group of subjects would be necessary to demonstrate bioequivalence with respect to the drug than with respect to the metabolite.