1. Division of Pharmacokinetics and Drug Therapy Department of Pharmaceutical Biosciences Uppsala University Estimating and forecasting in vivo drug disposition and effects using distributed computer systems Niclas Jonsson

2. Pharmacometrics Describes the dynamic interaction between drugs and individuals using quantitative models. The models are highly non-linear and are based on pato-physiological and pharmacological knowledge. The models are used in clinical drug development with the goal to make more efficient use of available data and to optimize future clinical trials.

3. Cross-disciplinary field Pharmacokinetics, Pharmacodynamics, Pharmacology Statistics/Mathematics (Theory, model formulation) Numerical issues (simulation, optimized computations, hardware strategies) (Pato-)physiologi (Disease states and progression) Pharmacometrics

4. Main application - NONMEM NON-linear Mixed Effects Modeling Old (fashioned) FORTRAN 77 program –First version appeared 1980 –Still the most widely used Single threaded…

5. Scope of problems to be solved Typical data consist of plasma concentration- drug effect-time data from tens to thousands of patients Run times for a single model fit varies depending on model complexity and amount of data <1 minShort >10 minModerate > DaysLong A typical analysis involves 30-100 runs

6. Future trends More computer intensive methods, e.g. –Stepwise variable selection (40-300 runs) –Cross-validation (100-500 runs) –Bootstrapping (200-2000 runs) –Monte Carlo simulations Combinations of the above More mechanistically based models, i.e. more complex models (>Days) Wider use of pharmacometrics in commercial and academic research. Parallelized “NONMEM”

7. Impact of parallelization/distributed computing Present software (NONMEM) does not allow for parallel execution of single runs. Most computer intensive methods do lend themselves to parallelization! Distributed computing solutions will allow us to investigate the properties of methods that will be tractable to the regular users 5+ years from now.

8. Our current environment 20+ users –The majority in applied work –~5 in theoretical research Cluster (since 2001) of 15+ CPUs –Load balancing –Parallel execution of multiple runs

9. Current hardware 5 Workstations 5 double CPU Computational Servers File Server Fast Ethernet Desktops/ Laptops 200 GB

10. Software Red Hat Linux 7.3 openMOSIX kluster patch for kernel 2.4.19 Perl 5.6.1 Perl-speaks-NONMEM+Parallel::Forkmanager –In house support library for parallelization of multiple NONMEM runs. –Recently completed.

11. Technical requirements Computational resources needed: –Fall 2003 and onwards, as much as possible… Inter-processor relative processing speed: –Inter-processor>processor Primary memory: –For some applications 1Gb is too little Secondary storage: –Up to 200 Gb for months Data access frequency: –? Status of software to be used: –Depends on porting issues (help needed?) –Late beta stage (PsN)