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Dose Adaptation Based on Pharmacometric Models
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
2009 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Model Based Dose Adaptation (English)
Abstract [en]

Many drugs exhibit major variability in both pharmacokinetic (PK) and pharmacodynamic (PD) parameters that prevents the use of the same dose for all patients. Variability can occur both between patients (IIV) as well as within patients over the course of time (IOV). In a drug with narrow therapeutic range and substantial IIV, dose selection may require individual adaptation. Adaptation can either be made before (a priori) or after (a posteriori) first drug administration. The former implies basing the dose on prior information known to be influential, such as kidney function indicators, weight or concomitant medication, whereas a posteriori dose adaptations are based on post-treatment observations. Often individualization cannot be based on the clinical outcome itself. In such cases, drug concentrations or biomarkers may be valuable for dose individualisation.

In this thesis two therapeutic areas where dosing is critical have been investigated regarding the possibilities of a priori and a posteriori dose adaptation; anticancer treatment where myelosuppression is dose limiting, and tacrolimus used for immunosuppression in paediatric transplantation. In tacrolimus previously published models were found to be of little value for dose adaptation in the early critical days post-transplantation. New PK models were developed and used to suggest new dosing regimens tailored for the paediatric population, recognizing the changing pharmacokinetics in the early time post-transplantation.

For several anticancer drugs covariates were identified that partly explained IIV in myelosuppression. IOV were found to be lower than IIV which implies that individual dose adaptations a posteriori can be valuable. Dose adaptation, using Bayesian principles in order to simultaneously minimise the risk of severe toxicity or subtherapeutic levels, was evaluated using simulations. Type and amount of data needed, as well as variability parameters influential on the outcome, were evaluated. Results show drug concentrations being of little value, if neutrophil counts are available.

The models discussed in this thesis have been implemented in MS Excel macros for Bayesian forecasting, to allow widespread distribution to clinical settings without necessitating access to specific statistical software.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2009. , p. 80
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 94
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-100569ISBN: 978-91-554-7488-1 (print)OAI: oai:DiVA.org:uu-100569DiVA, id: diva2:210545
Public defence
2009-05-15, B41, BMC, Dag Hammarsköldsväg, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-04-22 Created: 2009-04-02 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Population pharmacokinetics of tacrolimus in paediatric haematopoietic stem cell transplant recipients: New initial dosage suggestions and a model based dosage adjustment tool
Open this publication in new window or tab >>Population pharmacokinetics of tacrolimus in paediatric haematopoietic stem cell transplant recipients: New initial dosage suggestions and a model based dosage adjustment tool
2009 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 31, no 4, p. 457-466Article in journal (Refereed) Published
Abstract [en]

The population pharmacokinetics of tacrolimus was described in 22 paediatric haematopoietic stem cell transplant recipients and a model-based dosage adjustment tool that may assist with therapy in new patients was developed.  Patients received tacrolimus by continuous intravenous infusion (0.03mg/kg/day) starting two days before transplantation, with conversion to oral therapy 2-3 weeks post-transplant.  Population pharmacokinetic analysis was performed using NONMEM.  A dosage adjustment tool that searches for individual parameter estimates to describe concentration measurements, counter-balanced by the final population model, was created in Excel.  Typical clearance was 106 mL/h/kg0.75, typical distribution volume was 3.71 L/kg and typical bioavailability was 15.7%.  Tacrolimus clearance decreased with increasing serum creatinine and bioavailability decreased with post-operative day.  Predictions from the model showed that current intravenous dose recommendations of 0.03 mg/kg/day may produce potentially toxic drug concentrations in the patient population, whereas current oral conversion of four times the adjusted intravenous dose may lead to subtherapeutic concentrations. We suggest a dose of 0.035mg/kg0.75/day to ensure satisfactory levels, and an oral conversion factor of six times the intravenous dose.  A dosage adjustment tool was developed that is capable of suggesting an initial infusion rate based on patient weight and serum creatinine and of devising a further individualised dosage as individual drug concentration measurements become available.  The tool also allows the clinicia to graphically examine the concentration-time profile of tacrolimus under different infusion rates, with or without a loading dose.

Place, publisher, year, edition, pages
Philadelphia PA, US: Lippincott Williams & Wilkins, 2009
Keywords
tacrolimus, pediatric hematopoietic stem cell transplant, population pharmacokinetics, Bayesian forecasting, dosage prediction
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-100505 (URN)000268567400006 ()
Available from: 2009-04-01 Created: 2009-04-01 Last updated: 2018-01-13Bibliographically approved
2. Population pharmacokinetics of tacrolimus in paediatric liver transplant recipients: a model to describe early post-transplantation apparent clearance
Open this publication in new window or tab >>Population pharmacokinetics of tacrolimus in paediatric liver transplant recipients: a model to describe early post-transplantation apparent clearance
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(English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143Article in journal (Refereed) Submitted
Abstract [en]

 

In this study 1) the predictive capacity of two previously derived population pharmacokinetic models of tacrolimus in paediatric liver transplant recipients were tested during Bayesian forecasting 2) a new population pharmacokinetic model was developed focusing on the immediate post-transplant period and 3) this new model was applied in a simulation exercise to devise a new dosing scheme for initial oral dosing of tacrolimus.  Pharmacokinetic, demographic and covariate data were collected retrospectively from patient records.  The Abbottbase PKS program was used for Bayesian forecasting.  Actual tacrolimus concentrations were compared to those predicted by the program and bias and precision determined.  The NONMEM program was used for building of a new population pharmacokinetic model.  Factors screened for influence on the pharmacokinetic parameters were weight, age, sex, post-operative day, whole/cut-down donor liver, haematocrit, serum albumin, bilirubin, serum creatinine, creatinine clearance, liver function tests and country of origin.  Data were collected from 20 patients for Bayesian forecasting and from 73 patients for population pharmacokinetic modelling.  Predictive performance of the two previous population models was poor in the immediate post-transplant period (range of precision, bias).  Tacrolimus pharmacokinetics appeared to change rapidly over this period.  During the first and third month after transplantation use of only one previous sample during Bayesian forecasting providing the best predictive performance.  The final population model estimated a typical apparent clearance of tacrolimus of 0.148 L/h/kg0.75 immediately following the transplantation, increasing to a maximum of 1.37 L/h/ kg0.75 and typical apparent distribution volume of 27.2 L/kg.  An alternative initial dosing schedule was developed based on an initial loading dose followed by a maintenance dose that increased with time, with drug dosing based on allometric scaling.

 

Place, publisher, year, edition, pages
Hoboken NJ, US: Wiley-Blackwell
Keywords
tacrolimus, paediatric liver transplantation, population pharmacokinetics, Bayesian forecasting, dosage prediction
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-100509 (URN)
Available from: 2009-04-07 Created: 2009-04-01 Last updated: 2018-01-13Bibliographically approved
3. Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs
Open this publication in new window or tab >>Population pharmacokinetic-pharmacodynamic model for neutropenia with patient subgroup identification: comparison across anticancer drugs
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2006 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 12, no 18, p. 5481-5490Article in journal (Refereed) Published
Abstract [en]

Purpose: Cancer chemotherapy, although based on body surface area, often causes unpredictable myelosuppression, especially severe neutropenia. The aim of this study was to evaluate qualitatively and quantitatively the influence of patient-specific characteristics on the neutrophil concentration-time course, to identify patient subgroups, and to compare covariates on system-related pharmacodynamic variable between drugs.

Experimental Design: Drug and neutrophil concentration, demographic, and clinical chemistry data of several trials with docetaxel (637 patients), paclitaxel (45 patients), etoposide (71 patients), or topotecan (191 patients) were included in the covariate analysis of a physiology-based pharmacokinetic-pharmacodynamic neutropenia model. Comparisons of covariate relations across drugs were made.

Results: A population model incorporating four to five relevant patient factors for each drug to explain variability in the degree and duration of neutropenia has been developed. Sex, previous anticancer therapy, performance status, height, binding partners, or liver enzymes influenced system-related variables and alpha(1)-acid glycoprotein, albumin, bilirubin, concomitant cytotoxic agents, or administration route changed drug-specific variables. Overall, female and pretreated patients had a lower baseline neutrophil concentration. Across-drug comparison revealed that several covariates (e.g., age) had minor (clinically irrelevant) influences but consistently shifted the pharmacodynamic variable in the same direction.

Conclusions: These mechanistic models, including patient characteristics that influence drug-specific parameters, form the rationale basis for more tailored dosing of individual patients or subgroups to minimize the risk of infection and thus might contribute to a more successful therapy. In addition, nonsignificant or clinically irrelevant relations on system-related parameters suggest that these covariates could be negligible in clinical trails and daily use.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-100514 (URN)10.1158/1078-0432.CCR-06-0815 (DOI)000240714400033 ()17000683 (PubMedID)
Available from: 2009-04-07 Created: 2009-04-01 Last updated: 2018-01-13Bibliographically approved
4. Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression
Open this publication in new window or tab >>Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression
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2010 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 65, no 5, p. 839-848Article in journal (Refereed) Published
Abstract [en]

Purpose: A previously developed semi-physiological model of chemotherapy-induced myelosuppression has shown consistent system-related parameter and inter-individual variability (IIV) estimates across drugs. A requirement for dose individualization to be useful is relatively low variability between treatment courses (IOV) in relation to IIV. The objective of this study was to evaluate and compare magnitudes of IOV and IIV in myelosuppression model parameters across six different anti-cancer drug treatments.Methods: Neutrophil counts from several treatment courses following therapy with docetaxel, paclitaxel, epirubicin-docetaxel, 5-fluorouracil-epirubicin-cyclophosphamide, topotecan and etoposide were included in the analysis. The myelosuppression model was fitted to the data using NONMEM VI. IOV in the model parameters baseline neutrophil counts (ANC0), mean transit time through the non-mitotic maturation chain (MTT) and the parameter describing the concentration-effect relationship (Slope) were evaluated for statistical significance (P < 0.001).Results: IOV in MTT was significant for all the investigated datasets, except for topotecan, and was of similar magnitude (8-16 CV %). IOV in Slope was significant for docetaxel, topotecan and etoposide (19-39 CV %). For all six investigated datasets the IOV in myelosuppression parameters was lower than the IIV. There was no indication of systematic shifts in the system- or drug sensitivity-related parameters over time across data sets.Conclusion: This study indicates that the semi-physiological model of chemotherapy-induced myelosuppression has potential to be used for prediction of the time-course of myelosuppression in future courses and is thereby a valuable step towards individually tailored anticancer drug therapy.

Keywords
Hematologic toxicity, pharmacodynamics, NONMEM, inter-occasion variability, anti-cancer drugs
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-100507 (URN)10.1007/s00280-009-1089-3 (DOI)000274655500004 ()19680655 (PubMedID)
Available from: 2009-04-02 Created: 2009-04-01 Last updated: 2018-01-13Bibliographically approved
5. Model-Based Neutrophil-Guided Dose Adaptation in Chemotherapy: Evaluation of Predicted Outcome with Different Types and Amounts of Information
Open this publication in new window or tab >>Model-Based Neutrophil-Guided Dose Adaptation in Chemotherapy: Evaluation of Predicted Outcome with Different Types and Amounts of Information
2010 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 106, no 3, p. 234-242Article, review/survey (Refereed) Published
Abstract [en]

One of the most employed approaches to reduce severe neutropenia following anticancer drug regimens is to reduce the consecutive dose in fixed steps, commonly by 25%. Another approach has been to use pharmacokinetic (PK) sampling to tailor dosing, but only rarely have model-based computer approaches utilizing collected PK and/or pharmacodynamic (PD) data been used. A semi-mechanistic model for myelosuppression that can characterize the interindividual and interoccasion variability in the time-course of neutrophils following administration of a wide range of anticancer drugs may be used in a clinical setting for model-based dose individualization. The aim of this study was to compare current stepwise procedures to model-based dose adaptation by simulations, and investigate if the overall dose intensity in the population could be increased without increasing the risk of severe toxicity. The value of various amounts of PK- and/or PD-information was compared to standard dosing strategies using a maximum a posteriori procedure in NONMEM. The results showed that when information on neutrophil counts was available, the additional improvement from PK sampling was negligible. Using neutrophil sampling at baseline and an observation near the predicted nadir increased the number of patients in the target range by 27% in comparison with a one-sided 25% dose adjustment schedule, while keeping the number of patients experiencing severe toxicity at a comparable low level after five courses of treatment. High interindividual variability did not limit the benefit of model-based dose adaptation, whereas high interoccasion variability was predicted to make any dose adaptation method less successful. This study indicates that for successful model-based dose adaptation clinically, there is no need for drug concentration sampling, and that one extra neutrophil measurement in addition to the pre-treatment value is sufficient to limit severe neutropenia while increasing dose intensity.

National Category
Pharmacology and Toxicology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-100496 (URN)10.1111/j.1742-7843.2009.00520.x (DOI)000274454300014 ()20050841 (PubMedID)
Available from: 2009-04-01 Created: 2009-04-01 Last updated: 2018-01-13Bibliographically approved
6. A tool for neutrophil guided dose adaptation in chemotherapy
Open this publication in new window or tab >>A tool for neutrophil guided dose adaptation in chemotherapy
2009 (English)In: Computer Methods and Programs in Biomedicine, ISSN 0169-2607, E-ISSN 1872-7565, Vol. 93, no 3, p. 283-291Article in journal (Refereed) Published
Abstract [en]

Chemotherapy dosing in anticancer treatment is a balancing act between achieving concentrations that are effective towards the malignancy and that result in acceptable side-effects. Neutropenia is one major side-effect of many antitumor agents, and is related to an increased risk of infection. A model capable of describing the time-course of myelosuppression from administered drug could be used in individual dose selection. In this paper we describe the transfer of a previously developed semi-mechanistic model for myelosuppression from NONMEM to a dosing tool in MS Excel, with etoposide as an example. The tool proved capable to solve a differential equation system describing the pharmacokinetics and pharmacodynamics, with estimation performance comparable to NONMEM. In the dosing tool the user provides neutrophil measures from a previous treatment course and request for the dose that results in a desired nadir in the upcoming course through a Bayesian estimation procedure.

Keywords
dose adaptation, myelosuppression, pharmacodynamics, biomarker
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-100513 (URN)10.1016/j.cmpb.2008.10.011 (DOI)000263938100007 ()19084287 (PubMedID)
Available from: 2009-04-07 Created: 2009-04-01 Last updated: 2018-01-13Bibliographically approved

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