CYP3A4 phenotyping with midazolam to predict sunitinib exposure.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2592-2592
Author(s):  
Nielka P van Erp ◽  
Djoeke de Wit ◽  
Alex Sparreboom ◽  
Jan den Hartigh ◽  
Margret den Hollander ◽  
...  
Keyword(s):  
Steady State ◽  
Drug Exposure ◽  
Linear Regression Analysis ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Considerable Proportion ◽  
Cyp3a4 Activity ◽  
Standard Dosage ◽  
Patients At Risk ◽  
The Relationship

2592 Background: Patients treated with sunitinib show high inter-patient variability in drug exposure (40-60%), which is largely unexplained. Since sunitinib is metabolized by CYP3A4, variability in the activity of this enzyme may explain a considerable proportion of the observed variability. We therefore prospectively studied the relationship between CYP3A4 activity and systemic exposure to sunitinib. Methods: In fifteen patients treated with sunitinib in a four weeks “on” – two weeks “off” regimen the pharmacokinetics of sunitinib and its active metabolite SU12662 were assessed. To determine sunitinib+SU12662 steady-state exposure, samples were collected over 24hrs after at least 14 days of sunitinib therapy. To assess CYP3A4 activity, midazolam 7.5mg orally was administered on the final day of the two weeks “off”. Plasma concentrations were measured over a period of 7hrs to determine midazolam exposure. Exposures (AUC) were calculated using a trapezoidal approach (Phoenix WinNonlin v6.3). The relationship between CYP3A4 activity (midazolam exposure) and sunitinib+SU12662 exposure was determined by linear regression analysis. The percentage of variability in sunitinib+SU12662 exposure that could be explained by CYP3A4 activity was calculated by Pearson’s correlation. In addition, the correlation between sunitinib+SU12662 Ctrough levels and sunitinib+SU12662 exposure was assessed. Results: A strong correlation between midazolam exposure (AUC0-7hr) and steady-state sunitinib+SU12662 exposure (AUC0-24hr) was found (p= 0.002); CYP3A4 activity explained 55% of the observed inter-patient PK variability of sunitinib+SU12662. Furthermore sunitinib+SU12662 Ctrough levels were highly predictive (96%) for overall sunitinib+SU12662 exposure (AUC0-24hr). Conclusions: Midazolam as a phenotyping probe could be useful before start of sunitinib therapy to identify patients at risk for under- respectively overtreatment at a standard dosage regimen. Therefore, CYP3A4 phenotyping could be useful to individualize sunitinib therapy. Additionally, sunitinib+SU12662 trough levels are highly predictive for sunitinib+SU12662 exposure and thus can be used for monitoring and guiding sunitinib therapy in clinical practice. Clinical trial information: NCT01743300.

A System for Individualized Dosing of Intravenous Aminophylline Using a Programmable Calculator

PEDIATRICS ◽  
1984 ◽  
Vol 73 (1) ◽  
pp. 64-67
Author(s):  
J. Chris Mitsuoka ◽  
Richard J. Fleck
Keyword(s):  
Steady State ◽  
Serum Sample ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Dose Administration ◽  
Programmable Calculator ◽  
Concentration Determination ◽  
A Value ◽  
Individualized Dosing ◽  
History Of

A program that calculates a value of clearance for an individual patient prior to reaching steady state in the early stages of aminophylline therapy is presented. The program is written for the Texas Instruments TI-59 programmable calculator and may be used with or without the PC-100C printer. The program can provide clinically useful information concerning projected plasma concentrations prior to reaching steady state with an accurate history of the dose administration and serum concentration determination. If the patient has not received xanthene therapy prior to admission, only one serum sample is required. If there has been prior drug exposure, a second serum sample is required. An iterative technique, which would be impractical to use without calculator assistance, is employed to make these determinations.

Monitoring plasma concentrations of psychotropic drugs

1974 ◽  
Vol 12 (2) ◽  
pp. 6-8
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Tissue Concentration ◽  
Plasma Concentrations ◽  
Water Concentration ◽  
Plasma Samples ◽  
Active Metabolites ◽  
The Relationship ◽  
The Brain ◽  
Reliable Methods

Techniques are now available for estimating the plasma concentration of several drugs used in psychiatry. These techniques are clearly important for research but they can hardly be expected to improve the clinical management of patients unless the estimation is sensitive, reliable and reasonably quick; the method should be specific for the particular drug but should also specifically estimate any active metabolites. Even when reliable figures have been obtained, much more information is needed before they can be interpreted. The relationship between plasma (or plasma water) concentration and relevant tissue concentration (e. g. in the brain) must be known. Plasma samples should be taken at appropriate times, e. g. after the attainment of ‘steady-state’ conditions: plasma and tissue levels will then be in equilibrium. Diagnoses must be soundly based if inferences are to be drawn. Reliable methods of assessing clinical response must be available. These requirements pose difficult problems in psychiatry.

Pharmacokinetics and Pharmacodynamics of Imatinib in a Phase I Trial With Chronic Myeloid Leukemia Patients

2004 ◽  
Vol 22 (5) ◽  
pp. 935-942 ◽  
Author(s):  
Bin Peng ◽  
Michael Hayes ◽  
Debra Resta ◽  
Amy Racine-Poon ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
Steady State ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Drug Exposure ◽  
Dose Range ◽  
Once Daily ◽  
Concentration Time ◽  
The Relationship ◽  
Dose Proportional

Purpose To evaluate the basic pharmacokinetic (PK) characteristics of imatinib mesylate and assess the relationship between the PK and pharmacodynamic (PD) properties of the drug. Patients and Methods The PK and PD properties of imatinib were investigated during a phase I trial that included 64 adult patients with Philadelphia chromosome–positive leukemias. Patients received imatinib orally once or twice daily. PK parameters of imatinib, derived from the plasma concentration–time curves, were determined. PD response, defined as the WBC after 1 month of treatment with imatinib, was used to develop an efficacy model. A maximum inhibition–effect model was used to describe the relationship between reduction in WBC and drug exposure parameters. Results Imatinib exposure was dose proportional after oral administration for the dose range of 25 to 1,000 mg. There was a 1.5- to three-fold drug accumulation after repeated once-daily dosing. Mean plasma trough concentration was 0.57 μg/mL (approximately 1 μmol/L) 24 hours after administration of 350 mg of imatinib at steady-state, which exceeds the 50% inhibitory concentration required to inhibit proliferation of Bcr-Abl–positive leukemic cells. Analysis of PK/PD relationships indicates that the initial hematologic response depends on the administered dose for patients with chronic myeloid leukemia. Conclusion Drug exposure (area under the concentration-time curve) is dose proportional for the dose range of 25 to 1,000 mg, and there is a 1.5- to three-fold drug accumulation at steady-state after once-daily dosing. Analysis of the relationship between PD (WBC reduction) and PK parameters at steady-state indicates that a dose of 400 mg or greater is required for maximal PD effect.

scholarly journals Exposure-Response Relationships for Isavuconazole in Patients with Invasive Aspergillosis and Other Filamentous Fungi

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Amit V. Desai ◽  
Laura L. Kovanda ◽  
William W. Hope ◽  
David Andes ◽  
Johan W. Mouton ◽  
...  
Keyword(s):  
Steady State ◽  
Invasive Aspergillosis ◽  
Filamentous Fungi ◽  
Aspartate Aminotransferase ◽  
Drug Exposure ◽  
Fungal Infections ◽  
Plasma Concentrations ◽  
Water Soluble ◽  
Therapeutic Drug ◽  
Exposure Response

ABSTRACT Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.

scholarly journals Estimation of Pharmacokinetic Parameters of Continuous Intravenous Flucloxacillin infusion in the Outpatient Settings (PKFLUCLOX)

2018 ◽  
Author(s):  
Nilar Lwin ◽  
Zheng Liu ◽  
Mark Loewenthal ◽  
Pauline Dobson ◽  
Ji Woong Yoo ◽  
...  
Keyword(s):  
Steady State ◽  
Continuous Infusion ◽  
Time Course ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Device Removal ◽  
Standard Dosage

Flucloxacillin, a beta-lactam antibiotic of the penicillin class, is considered first line therapy for methicillin sensitive Staphylococcus aureus (MSSA) in Australia. At our tertiary referral hospital in the home (HITH) program, it has been prescribed in a standard dosage of 8 grams per day by continuous infusion for more than 20 years. The aim of this observational study was to characterize the pharmacokinetic profile of flucloxacillin in patients who receive continuous infusion in the HITH setting, and to undertake population pharmacokinetic analysis performed with NONMEM software by comparing various structural models. This study utilised flucloxacillin concentrations from 44 separate specimens obtained from 23 patients. Twenty-five of these were collected immediately after elastomeric device removal, representing steady-state concentrations, and the remaining 19 were each collected at least 45 minutes after device removal to determine clearance of the drug. Plasma concentrations ranged from 13 to 194 mg/L with median steady-state concentration of 51.5 mg/L and inter-quartile range of 24.6 mg/L. The time-course of flucloxacillin was best described by a 1-compartment model. The best three covariates, CrCL (ΔOFV= -11.7), eGFR (ΔOFV= -5.9) and serum albumin (ΔOFV= -5.8) were found to be equivalent in terms of decreasing the OFV. CrCL was superior in explaining inter individual variability. The best model for flucloxacillin clearance was a one compartment model with CrCL as the sole covariate. The estimated population parameters were 9.5 L for volume of distribution and 8.1 L/h for flucloxacillin clearance.

P093 IDENTIFICATION OF PATIENTS AT RISK OF SUBTHERAPEUTIC DRUG EXPOSURE PRIOR TO INITIATION OF CERTOLIZUMAB PEGOL THERAPY FOR THE TREATMENT OF CROHN’S DISEASE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S69-S70
Author(s):  
Pavine Lefevre ◽  
Leonardo Guizzetti ◽  
Brian Feagan ◽  
Anca Pop ◽  
Mohamed Yassine ◽  
...  
Keyword(s):  
At Risk ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Drug Exposure ◽  
Certolizumab Pegol ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Clinical Variables ◽  
Therapy Initiation ◽  
Patients At Risk

Abstract Background Certolizumab pegol (CZP) is effective treatment for moderately-to-severely active Crohn’s disease (CD)1, 2 at approved subcutaneous doses of 400 mg on weeks 0, 2 and 4 (induction) and every 4 weeks thereafter (maintenance). Prior research has demonstrated a relationship between CZP drug exposure and outcomes, with higher plasma CZP concentrations during induction and maintenance therapy associated with more favorable clinical, endoscopic and biologic (C-reactive protein [CRP], fecal calprotectin [FC]) disease outcomes.3 Increased drug clearance is the driver of subtherapeutic CZP concentrations, although the identification of patients at risk for accelerated clearance prior to therapy initiation has not previously been possible. Methods A population pharmacokinetic model4 was used to estimate baseline CZP clearance (i.e., at the time of therapy initiation) using baseline clinical variables (i.e., gender, body weight, albumin and CRP concentration) available from patients with CD previously included in nine randomized, controlled, phase 2 and 3 trials (N=2157). Baseline CZP clearance was compared between patients who achieved observed Week 6 CZP plasma concentrations previously associated with meaningful clinical (>36 μg/mL for Crohn’s Disease Activity Index [CDAI] ≤ 150), biologic (>44 μg/mL for FC ≤ 250 μg/g) and composite clinical and biologic (>48 μg/mL for CDAI ≤ 150 and FC ≤ 250 μg/g) outcomes at Week 6. Receiver operating characteristic curve analysis identified baseline CZP clearance thresholds associated with effective CZP concentrations at Week 6. Results Baseline CZP clearance was significantly higher in patients not achieving effective Week 6 CZP plasma concentration thresholds of 36 μg/mL, 44 μg/mL and 48 μg/mL compared to patients who achieved these thresholds (Figure 1; p<0.0001 for all comparisons). Baseline CZP CL of ≥ 0.5 L/day was associated with subtherapeutic observed Week 6 CZP plasma concentrations. The sensitivity, specificity, likelihood ratios and area under the concentration curves for the association between baseline CZP clearance and observed Week 6 CZP concentration thresholds are shown in Table 1. Conclusion Patients with CD who have accelerated baseline CZP clearance are at risk of subtherapeutic CZP concentrations. Clearance can be calculated using baseline clinical variables and would allow for identification of patients for whom therapeutic CZP concentrations may be achieved with current approved dosing. Implementing therapeutic drug monitoring may increase the likelihood of achieving therapeutic drug exposure during induction as well as treatment success. References

Using PBPK Modeling to Predict Drug Exposure and Support Dosage Adjustments in Patients With Renal Impairment: An Example with Lamivudine

2020 ◽  
Vol 17 (3) ◽  
pp. 387-396 ◽  
Author(s):  
Kushal Shah ◽  
Briann Fischetti ◽  
Agnes Cha ◽  
David R. Taft
Keyword(s):  
Renal Impairment ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Systemic Exposure ◽  
Transcriptase Inhibitor ◽  
Pbpk Modeling ◽  
Published Data ◽  
Post Dose ◽  
Model Simulations ◽  
The Impact

Background: Lamivudine is a nucleoside reverse transcriptase inhibitor used to treat HIV and hepatitis B. It is primarily cleared by the kidney with renal secretion mediated by OCT2 and MATE. Objective: To use PBPK modeling to assess the impact of renal impairment on lamivudine pharmacokinetics using the Simcyp® Simulator. Methods: The model incorporated the Simcyp® Mechanistic Kidney Model option to predict renal disposition. The model was initially verified using the Simcyp® Healthy Volunteer population. Two discrete patient populations were then created for moderate (GFR 10-40 mL/min) and severe (GFR < 10 mL/min) renal failure (RF), and model simulations were compared to published data. The developed model was then utilized in a clinical study evaluating the clinical experience and plasma exposure of lamivudine when administered at higher than recommended doses to HIV-infected patients with varying degrees of renal impairment. Results: Predicted systemic exposure metrics (Cmax, AUC) compared favorably to published clinical data for each population, with the following fold errors (FE, ratio of predicted and observed data) for Cmax/AUC: Healthy Volunteers 1.04/1.04, Moderate RF 1.03/0.78, Severe RF 0.89/0.79. The model captured lamivudine plasma concentrations measured pre- and post-dose (0.5-1.5hr) in study participants (n = 34). Model simulations demonstrated comparable systemic profiles across patient cohorts, supporting the proposed dosage adjustment scheme. Conclusion: This study illustrates how PBPK modeling can help verify dosing guidelines for patients with varying levels of renal impairment. This approach may also be useful for predicting potential changes in exposure during renal insufficiency for compounds undergoing clinical development.

Dextromethorphan phenotyping as a test for prediction of tamoxifen (TAM) activation in breast cancer patients receiving adjuvant hormone therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13019-e13019
Author(s):  
Milena Gusella ◽  
Laura Bertolaso ◽  
Felice Pasini ◽  
Yasmina Modena ◽  
Antonio Bononi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Steady State ◽  
Cancer Patients ◽  
Plasma Levels ◽  
Linear Regression Analysis ◽  
Plasma Concentrations ◽  
Breast Cancer Patients ◽  
Active Metabolites ◽  
Adjuvant Hormone Therapy ◽  
State Plasma

e13019 Background: TAM is mainly metabolized by CYP2D6 to form its most active metabolites, 4hydroxy-tamoxifen (4OH-T) and endoxifen (END). Because of its long half-life, steady state is reached after around 4 months of continuous intake. The wide variable inter-patient activity of CYP2D6 might influence drug efficacy. A multi-institutional study in north Italy is evaluating the relationship between END levels and outcome. As a part of it, we investigated the role of dextromethorphan (DM), a probe drug for CYP2D6 enzymatic activity, as a potential phenotyping test for TAM activation. Methods: Twenty-nine breast cancer patients (75% postmenopausal) on adjuvant TAM therapy (20 mg/die) were investigated. They received a single dose (15 mg) of oral DM before starting TAM and their urines were collected over the10 following hours. Simultaneous quantitative determination of DM and its metabolite dextrorphan (DO) was performed in urines to estimate their log transformed metabolic ratio (LMR=logDM/DO). After 4 months a blood sample was collected to characterize TAM exposure at steady state; plasma levels of TAM, END, 4OH-T and the non active END precursor N-desmethyltamoxifen (NDT) were quantified by HPLC. Linear regression analysis and t test were performed for correlating LMR and drug plasma levels. Results: LMR varied between -2.15 and 0.90 (median: -1.37) while steady state plasma levels of END varied between 1.9 and 15.0 ng/ml (median: 4.36) and 4OH-T between 0.9 to 3.1 ng/ml (median:1.72). A significant correlation (r = 0.56; p= 0.0013) was found between LMR and END plasma concentrations. The patients with high LMR (> median value), compared to patients with low LMR, had lower END (3.7 vs 7.5 ng/ml, p=0.0003), lower 4OH-T (1.6 vs 2.1 ng/ml, p=0.04) and, accordingly, higher NDT (291.2 vs 198.2 ng/ml, p=0.025). Conclusions: DM/DO urine ratio obtained before starting therapy correlates with TAM biotransformation activity and can predict steady state active metabolites exposure in individual patients. This phenotyping test is fast, simple and unexpensive and could contribute to the personalization of adjuvant breast cancer treatment. Funded by Regione Veneto.

How to predict sunitinib exposure and toxicity: A pharmacokinetic-pharmacodynamic study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15592-e15592 ◽  
Author(s):  
Anatole Cessot ◽  
Celine Narjoz ◽  
Audrey Thomas-Schoemann ◽  
Pascaline Boudou-Rouquette ◽  
Jean-Louis Golmard ◽  
...  
Keyword(s):  
Genetic Polymorphisms ◽  
Drug Exposure ◽  
Renal Carcinoma ◽  
Plasma Concentrations ◽  
Individual Variability ◽  
Severe Toxicity ◽  
Daily Dose ◽  
Grade 3 ◽  
Vegfr Inhibitor ◽  
The Relationship

e15592 Background: Su (su), a tyrosine kinase VEGFR inhibitor, is subject to large inter-individual variability in drug exposure (AUC) and toxicity. We investigated the variability factors influencing AUC as well as the relationship between acute severe toxicity, AUC and genetic polymorphisms in adult cancer patients under su. Methods: The plasma concentrations of su and SU12662 (active metabolite) were assessed on day 7 and 21 of the first cycle. For variability investigation, su, SU 12662 and composite AUC (su+SU12662) were estimated from a population approach, then normalized to 50mg daily dose of su. Genetic polymorphisms for CYP3A4, CYP3A5, CYP1A2, NR1I2, NR1I3, P-gP and BCRP1 were analyzed. Clinical acute toxicity was graded using the NCI 4.0 scale on days 7 and 21. Baseline clinical and biologic characteristics including the lean body mass (LBM), absolute AUC and pharmacogenetic variants were tested univariately for association with toxicities. LBM was simply estimated from gender, height and weight. Candidate variables with p<0.1 were analyzed in a multivariate analysis. Results: Ninety-two pts were evaluable whose 66 for genetic analysis. Sixty-three percent of pts were male, 71% were PS 0-1, 60% had renal carcinoma. A large interindividual variability in normalized composite AUC was observed (CV=40%); LBM and ABCG2polymorphism (421C>A) were identified as major variability factors (p<0.0001 and p=0.014, respectively). Grade³2 hypertension, thrombocytopenia and hand-foot skin reaction were observed in 50, 11 and 10% respectively. Age (OR=1.47 [1.01-2.15], p=0.048) and su AUC (OR=1.16 [1.05-1.28], p=0.005) were independently associated with grade³3 toxicity within the first month, and SU12662 AUC with grade 3 thrombocytopenia (OR=1.27 [1.03-1.57], p=0.028). A formula was built from LBM to define the initial su dose to reach a target composite AUC of 1500ng/mL.h. Conclusions: Monitoring sunitinib and SU12662 exposure may be helpful to prevent severe toxicities. The estimation of LBM, based on gender and anthropometric characteristics, is useful to determine the initial daily dosing of sunitinib.

Evidence for Therapeutic Drug Monitoring of Targeted Anticancer Therapies

2012 ◽  
Vol 30 (32) ◽  
pp. 4017-4025 ◽  
Author(s):  
Bo Gao ◽  
Shang Yeap ◽  
Arthur Clements ◽  
Bavanthi Balakrishnar ◽  
Mark Wong ◽  
...  
Keyword(s):  
Steady State ◽  
Therapeutic Drug Monitoring ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Clinical Care ◽  
Systemic Exposure ◽  
Current Evidence ◽  
Therapeutic Drug ◽  
Routine Practice ◽  
Intravenous Injections

Therapeutic drug monitoring (TDM) provides valuable guidance for dose adjustment of antibiotics, immunosuppressives, antiepileptics, and other drugs, but its use for traditional anticancer therapies has been limited. Perhaps the most important obstacle is the impractical requirement of multiple blood samples to adequately define systemic exposure of drugs that have a short elimination half-life and are given by intermittent intravenous injections. However, the newer targeted anticancer therapies have different pharmacokinetic (PK) and dosing characteristics compared with traditional cytotoxic drugs, making it possible to estimate the steady-state drug exposure with a single trough-level measurement. Recent evidence indicates that certain PK parameters, including trough levels, are correlated with clinical outcomes for many of these agents, including imatinib, sunitinib, rituximab, and cetuximab. Although the current evidence is insufficient to mandate TDM in routine practice, a concerted investigation should be encouraged to determine whether the steady-state trough measurements of targeted agents will have a practical place in the clinical care of patients with cancer.

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