Outline. How should we do TDM? Does the evidence support TDM outcomes

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1 Overcoming Barriers to TDM: Information and the TDM Renaissance How to integrate PK intelligence with routine clinical data Alexander A. Vinks, PharmD, PhD, FCP Professor, Director Pediatric Pharmacology Research Unit (PPRU) Cincinnati Children s Hospital and Medical Center Outline Importance of the right information for proper interpretation Numbers only TDM is not effective Does the evidence support TDM outcomes? UNC-CERT CERT initiative to develop Model TDM services in Pediatrics Our experience at Cincinnati Children s Therapeutic Drug Monitoring is the measurement made in the laboratory of a parameter which, with appropriate interpretation, will directly influence prescribing procedures IFCC/IA-TDMCT Joint Committee 1993 How should we do TDM? Not to check numbers or Therapeutic Ranges To describe and understand Drug PK/PD Behavior Collect informative data to use as Bayesian priors for designing model-based, individualized dosing regimens Change passive Monitoring to active Management Phenytoin model-based interpretation Epilepsy pt (F, 33yr) 3 mg/kg/day Start iv -> po 1mg/L = Therapeutic Single numbers do not give the whole picture! Phenytoin (mg/l) Does the evidence support TDM outcomes Methotrexate Evans et al. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med 1998;338(8):499-. Aminoglycosides Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal l inhibitory concentration. J Infect Dis 1987;(1):93-9 van Lent-Evers et al. Impact of goal-oriented oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost- effectiveness analysis. Ther Drug Monit 1999;21(1): Other Ensom et al. Clinical pharmacokinetics in the 21st century. Does the evidence support definitive outcomes? Clin Pharmacokinet 1998;34(4): Grasela et al. Clin Pharmacokinet 1983;8(4):3-64

2 Running a centralized TDM service Specific Aims TDM Study Affiliated Hospitals Hospital 3 Hospital 2 Hospital 1 Hospital Hospital 4 & Children's PK - TDM laboratory Implementation of goal-oriented oriented model- based dosing Pro-Active guidance vs. non-guided TDM Outcomes - clinical and economical benefits data Target concentration PK model PK dosing Van Lent et al. Cost-effectiveness of model based TDM. TDM 1999;21:63-73 Demographic data patients Bayesian Adaptive Control Variable Intervention Controls Model based prediction Individualized Total patients Included patients Infection on admission Male / Female Age (yr) (46%) / 67. (± 17.) (49%) 67/6 67. (± 17.2) Weight (kg) 69.1 (± 13.2) 69.8 (± 17.) 7-yr yr-old, 8 kg. Gram-neg infection. Gentamicin: 24mg load, 18mg q12h maintenance Distribution of Peaks & Troughs Active Therapeutic Monitoring benefits patient outcome 24 ** non-guided TDM ATM non-guided TDM ** ATM % of patients n = 62 vs ± 1.4 vs 12.6 ±.8 days p <.1 controls deceased patients Time in hospital (days) TDM cost-effectiveness study; van Lent-Evers et al. Ther Drug Monit 1999;21:63-73

3 Store and analyze data in our Heads, on Paper or in Computers BUT where s the link? UNC-CERT CERT Project Development of Model TDM services Establish policies to collect, interpret and report drug concentrations using a secure web-based based data collection tool Develop educational materials and methods to teach proper TDM techniques in pediatrics Compare outcomes for no TDM, numbers only or consultation by the model TDM service Data Clinical Data Base PK-PD-PG models reports Interpretation Eye Sis : Integrating Clinical Information System (ICIS) COE Clinical order Entry NetAccess - Lab Results Clinical Documentation Charting Med/IV Charting electronic Medication Adminsitration Record PACS Picture Archiving and Communication System Toward single portal for all platforms Data base structure at CCHMC KIDS COE CORE SQL ADT Clinical Lab Cerner Openlink LCR NetAccess I yr Info Liver CF Neuro Development of Web-based based tools Web-based based Liver Portal with Immunosuppressant TDM data

4 Over-use and over-interpretation of drug levels Dates and timing of samples Fixed monitoring strategies often lead to bad decision making Treating the level rather than treating the patient NO pharmacokinetic interpretation involved Tacrolimus (µg/l) Samples sorted by date Fig. Five patients with near daily tacrolimus TDM Tacrolimus (µg/l) Sample numbers (by patient name) One month of routine tacrolimus TDM at CCHMC. Data are 26 concentrations in 88 patients Time of day (h) Daily measurements Early morning troughs But also other times No demographic data No dosing information Interpretation? Liver Transplant - case history Liver Transplant - PK Evaluation 1 yr old African American boy Transplant 1998 Rejection July 1998 & December 2 FK levels <1. µg/l at 4 mg bid Fluctuating levels between 1.- µg/l Q: Compliance high clearance other? yr old African American boy Transplant 1998 Rejection July 1998 & December 2 FK levels <1. µg/l at 4 mg bid Fluctuating levels between 1.- µg/l Q: Compliance high clearance other? PK model based interpretation PI monitoring Columbus Children s Samples and dosing information was collected on patients (age yr) Most (1/) were prescribed nelfinavir with widely varying dose: range 33 to 146 mg/kg/day. Measured blood levels in single samples were: none detected 9.9 µg/ml. 24% (6/2) of pediatric samples were none detected vs. 33% of adult samples (96/293) Four patients with initially ND levels had multiple levels (one pre-dose and two post-dose samples) drawn over time Walson et al. Ther Drug Monit 23 in press

5 Nelfinavir PK Model-based Interpretation Usefulness of Population PK models Example: Nelfinavir Child (4 yr) receiving NFV 112 mg/kg/day Trough none detectable Dose per G-tube G good compliance Medication being flushed with water - changed to formula On re-testing strain resistant to nelfinavir Indinavir (mg/l) Time (h) PK model: CL/F 1. L/Kg/h (CV 3%) V/F 3.9 L/Kg (CV 4%) Ka.3 1/h (CV 3%) Nelfinavir (mg/l) Time (days) van Heeswijk et al. TDM 22;24(4): Cincinnati Children s Hospital Medical Center Conclusions TDM informatics is still in its infancy Passive monitoring should be replaced by active Management Need better tools to link all clinical data to drug behavior (PK) data Need to develop tools to link patient info with Population PK, Pharmacogenetics (PG), Adverse Events and Clinical Effects (PD) data Acknowledgements Phil Walson,, MD Shareen Cox, BS John Bucuvalas,, MD