1 Population Pharmacokinetics of Phenytoin in Saudi Patients Thamer M. Al-Shammary M.S candidate Supervised by Hisham S. Abou-Auda, Ph.D. Tawfeeq A. Al-Najjar, Ph.D.

2 Contents Introduction Objectives Methodology Results and discussion Conclusion

3 Introduction Chemistry Hydantoin-derivative anticonvulsant Insoluble in water Soluble in hot alcohol Pharmacology Anticonvulsant agent. Antiarrhythmic agent Class 1-B

4 Introduction Pharmacokinetics Absorption:Cap=92% Sus=100% (peak: 4 – 12 hr) (peak: 1- 3 hr) Distribution:V dss : 0.6 – 1.2 L/kg Crosses the Placenta Crosses into Breast Milk Half-life:22 hr

5 Introduction Pharmacokinetics MetabolismOxidation (Liver) Elimination:As HPPH metabolite in bile & urine <5% unchanged in urine

6 Introduction Therapeutic uses Generalized Tonic-Clonic (Grand mal) Simple and Complex Partial seizures. Prevention of seizures following trauma and neurosurgery. Status epilepticus. Ventricualr Arrhythmia. Adverse effects Dizzines, insomnia, headache, N, V, constipation Gingiva hyperplasia, Encephalopathy and nystagmus

7 Loading dose –15-20 mg/kg/day (in 3 divided doses) Maintenance dose ( mg/kg/day) –6 m-3 yr: –4-6 yr: –7-9 yr: –10-16 yr: Introduction Loading dose –15-20 mg/kg/day (in 3 divided doses) Maintenance dose –300 mg/day (or 5-6 mg/kg/day, as tid) Dosage Children Adults

8 Introduction Precautions and contraindications Hypersensitivity to phenytoin Severe liver disease Heart block, sinus bradycardia Pregnancy (category D) and lactation Use with caution in: DM Elderly Pts with porphyria

9 Introduction Drug interactions ethosuximidE INH Fluconazole Diazepam Estrogen CBZ Phenobarbital Rifampin Ethanol ( Alcohol ) Valproic acid Sodium valproate TCA,s ↓ PHT level or ↑ ↓ PHT level PHT level ↑

10 Population Pharmacokinetics Introduction Random Effects Fixed effects Underlying disease Age Weight Sex Intra- individual variability Inter- individual variability

11 Importance of Phenytoin monitoring Introduction Narrow therapeutic index Wide inter&intra- Individual differences Seizures development

12 Introduction Serum phenytoin level 0 10 Sub-therapeutic range Therapeutic range Far lateral nystagmus 45 o lateral gaze nystagmus and ataxia Status epilepticus and mental changes Death Mcg/ml

13 Introduction South African KmKm = 13.6  mol/L V max =6.5 mg/kg/day 37 pts 21 male 16 female 37 pts 21 male 16 female Prospective study For 1 year Prospective study For 1 year

14 Km= 3.67 mg/L Japan Introduction Vmax= 369 mg/day Retrospective study 220 pts 120 male 100 female 220 pts 120 male 100 female

15 Chinese Introduction

16 Objectives Determine the population pharmacokinetic parameters of phenytoin Compare the pharmacokinetic parameters for Saudi patients with other populations

17 Methodology

18 Data Collection form Lab Medical Records Coding Analysis Lab Medical Records Coding Data collection ( KKUH ) Methodology

19 Inclusion and Exclusion criteria Methodology Inclusion Exclusion Saudi Pts Saudi Pts Receive PHT ≥ 2 wks Receive PHT ≥ 2 wks Non-Saudi Pts Non-Saudi Pts Receive PHT ≤ 2 wks Receive PHT ≤ 2 wks

20 Data Analysis Methodology NCSSNONMEM SAAMSPSS WinNonMix

21 Results and Discussion

22 Results and discussion Value Item Mean ± S.D Age (yr) ± ± ± 0.27 Weight Height DEMOGRAPHIC CHARACTERISTICS 101Patients 58 Males (57.4%) 43 Females (42.6%)

23 JapanS.A Chinese Vm 6.5 mg/kg/ day Km 13.6  mol/l Km 3.67 mg/L Vm 369 mg/day VmKm Saudi