CLINICAL PIIAILMACOL¢)GY & THERAPEUTICS P 7 4 American Society for Clinical Pharmacology and Therapeutics F~BRUARY2003

PIII-43 PHARMACOKINETIC-PHARMACODYNAMIC ANALYSIS

OF DATA FROM A PHASE Ill TRIAL OF LINEZOLID IV/PO FOR THE TREATMENT OF RESISTANT GRAM-POSITIVE BACTERIAL INFECTIONS IN CHILDREN. M. Vo, PharmD, C. M. Rubino, PharmD, B. B. Cirincione, MA, J. Bruss, MD, MPH, G. L. Jungbluth, PhD, Cognigen Corporation, Pharmacia Corpora- tion, Buffalo, NY.

Purpose: Linezolid (LZD), the first approved oxazolidinone, is effective against gram-positive infections. Population PK/PD analy- ses of phase III data were conducted to evaluate exposure-response relationships in children to support a multiple-dosing regimen.

Method: Sparse sampling was obtained from patients aged birth to 11 years given 10mg/kg LZD every 8 hours. Patients were allowed to switch to oral (microencapsulated suspension) after six IV doses. Previously developed population PK models were used to predict individual PK parameters and exposure by Bayesian method. Rela- tionships between exposure and effectiveness (clinical/microbiolog- ical cure) and safety (hematologic labs, adverse events) were ex- plored graphically.

Result: Mean _+ SD age and weight were 35 -+ 38 months and 13 +- 11 kg. All models predicted individual concentrations with minimal bias and misspecification. Mean -+ SD AUC0-24 was 147 ÷ 87 ttg.h/mL, lower than adult exposure (179 _+ 62 b~g'h/mL). Pre- dicted time above MIC90 was 54 -+ 25% and independent of admin- istration route or age. End of treatment and follow-up clinical cure were 85% and 90%. Microbiologic success rate was 89%. There was no apparent association between exposure as measured by AUC and effectiveness or safety endpoints.

Conclusion: Previously developed models properly estimated ex- posure and verify dosing of 10 mg/kg every 8 hours in children aged birth to 11 years. Elimination of oral and IV linezolid is comparable. Effectiveness and safety were independent of exposure.

PIII-44 THE AUSTRALIAN PAEDIATR1C PHARMACOLOGY RE-

SEARCH UNIT (A-PPRU): A DEDICATED CLINICAL TRIALS CENTRE FOR CHILDREN. N. E. Cranswick, MB~BS~BS Royal Children's Hospital, Parkville, Australia.

In the past, drug studies in children have not been performed for both ethical and practical reasons. While this has been recognised for over 20 years, and the term "therapeutic orphan" coined, only in the last 5 yem's has this problem been addressed. The United States (US) has developed a series of paediatric trials centres coordinated by the National Institutes for Health. Australia was initially slow to respond although this need was recognised in 1996 with the release of an official government report on paediatric drug regulation.

The increasing need for adequate facilities resulted in three years of formal government funding, totalling up to $4.9 million, for a paediatric trials centre based upon the US model - The Australian Paediatric Pharmacology Research Unit. This facility incorporates a clinic space to conduct trials as well as areas for accommodation for parents. Full time dedicated research staff, with an expertise in paediatric clinical trials, manage the facility. The centre was to become self-funding in three years. Results

Following a series of incentives for pharmaceutical coutpanies to perform trials with new drugs in children, our paediatric hospital in Melbourne has seen a rapid increase in the number of paediatric clinical trials over 5 years. Despite only recently being funded, the centre has or is conducting 20 early phase studies in several areas of paediatrics and has become largely self-funded within two years of establishment.

PIII-45 DRUG-RELATED HOSPITAL ADMISSIONS: A PROSPEC-

TIVE CASE-BASED STUDY. P. Thuermann, MD, S. Schneeweiss, PhD, M. Hippius, PhD, A. Riethling, MD, J. Hasford, Prof., MD, Hospital Wuppertal, Harvard Medical School, University of Jena, University of Rostock, University of Munich, Wuppertal, Germany.

Drug-related hospital admissions (DRA) represent a major health problem and cost factor. In 2 German Pharmacovigilance centers all non-elective hospital admissions to medical wards were screened prospectively for adverse drug reactions (ADR) from Oct. 1997 to March 2000. Standardized causality assessment was performed ac- cording to Begaud. Data were submitted electronically to central quality assurance and the GelTnan drug authority (BfArM). Prescrip- tion data were obtained from regional pharmacy computing centers. For estimation of incidence, the exposed population was defined as medication users living in postal code areas contributing to the first 60 % of all cumulative hospital admissions. In 993 patients admission was caused by an ADR (2.4 % of all non electively admitted pa- tients). Per 10.000 patients treated with antithrombotics, 26.9 hospital admissions were calculated, incidence rates for NSAIDs came to 15.4, for oral antidiabetics to 6.3 and for insulin to 15.3. Incidence rates for ACE-inbibitors, calcium channel blocker, betablockers and digitalis preparations ranged between 5 and 8. Sensitivity analysis with regard to postal areas revealed comparable results. Quarterly estimated incidence rates showed adequate stability. The established system allows for rapid and high-quality ADR-reporting and reliable estimation of ADR incidences.

Supported by the BfArM, grant no. Fo 2.1-68502-201.

PIII-46 SAFETY AND EFFICACY OF CYCLOBENZAPRINE 5MG IN

ACUTE MUSCULOSKELETAL SPASM. S. Korn, MD, R. Tip- ping, MS, S. Van Belle, MS, E. Kobylinski, PharmD, P. E. Ciccone, MD, Merck Research Laboratories, Blue Bell, PA.

Two randomized, double-blind, parallel group studies were con- ducted to evaluate the safety and efficacy of eyclobenzaprine 5mg t.i.d. (CYC 5) for 7 days in patients with acute musculoskeletal spasm of neck/low back. Study 1 (n=737) compared CYC 10, CYC 5, and placebo (PBO); Study 2 (n 668) compared CYC 5, CYC 2.5, and PBO. Comparisons of CYC 5 and PBO in both studies showed statistically significant differences (p--<0.03) for all 3 primary patient- reported endpoint scales (Global Impression of Change, Medication Helpfulness, Relief from Starting Backache) at day 8. A greater reduction in physician-palpated muscle spasm was seen with CYC 5 than PBO. Study 1 showed similar results for CYC 10 and CYC 5 at all 3 primary endpoints, with significant differences compared to PBO by day 4. Median time to "a lot of''/ "complete" relief was 2 days less for CYC 5 than PBO. Study 2 showed CYC 2.5 was not consistently effective versus PBO. Most common adverse events in both studies were sedation and dry mouth (dose-related):

Adverse % PBO % CYC 2.5 % CYC 5 % CYC 10 Event (n=469) (n=223) (n=464) (n=249)

Sedation 9.6 19.7 29.1 37.8 Dry mouth 6.6 l 3.9 21.1 31.7 Fatigue 2.6 4.0 5.6 6.0 Headache 7.5 7.2 5.4 4.8

Sedation was generally mild, causing 4.9% discontinuation on CYC 10, versus 2.5% on CYC 5, and 0.5% on PBO.

Conclusions: CYC 5mg is clinically and statistically superior to PBO in acute back or neck muscle spasm, with CYC 5 efficacy similar to CYC 10. CYC 5 appeared to be less sedating than CYC 10.