1. Case studies Saila Antila, PhD WHO consultant Training workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence, Kiev 3.-7.10.2005

2. Case study 1 Characteristics of drug X half-life, conventional preparations: 4-6 h half-life from modified release preparations: 11-15 hours food decreases absorption of the drug innovator’s SPC: steady state concentrations are reached by the fourth day of the treatment

3. Case study 1 Modified release tablet The applicant has performed single dose, randomised, 2-period, cross-over study in fed state multiple dose, randomised, 2-period, cross-over study in fed state –first treatment period 4 days –second treatment period 3 days

4. Case study 1 Pharmacokinetic parameters, single dose, fed state TreatmentAUC 0-t (ng*h/ml) AUC 0-inf (ng*h/ml) C max (ng/ml) Test186 ± 56.2189 ± 57.914.8 ± 3.9 Reference187 ± 68.9194 ± 71.314.9 ± 4.1 Ratio (90 % CI) 96.8 (85.4-99.9) 92.3 (86.9-101.8) 97.2 (88.3-106.3)

5. Case study 1 Pharmacokinetic parameters, multiple dose, fed state Treat- ment AUC 0-τ (ng*h/ml) C min (ng*h/ml) C max (ng/ml) Fluctua -tion Test189 ± 712.16±1.0816.3 ± 5.9180 ± 48 Referenc e 190 ± 692.85±1.3516.7 ± 5.4174 ± 42 Ratio (90 % CI) 91.7 (88.3- 97.6) 80.1 (72.4- 90.5) 100.6 (93.8- 108.7) 116.7 (107.4- 125.4)

6. Case study 1 Weaknesses of the documentation study in fasting state is missing the second treatment period is too short  according to the originators SPC steady state is achieved by the fourth treatment day

7. Case study 2 Characteristics of drug Y active metabolite R- & S-enantiomers linear pharmacokinetics multiple strengths (0.5, 1 mg, 2 mg, 4 mg) antipsychotic agent

8. Case study 2 Immediate release capsule The applicant has performed one single dose study with 1 mg capsule

9. Case study 2 Pharmacokinetic parameters, single dose, fasting state, parent drug TreatmentAUC 0-t (ng*h/ml) AUC 0-inf (ng*h/ml) C max (ng/ml) Test4630± 5904720± 618569 ±340 Reference4670± 5304780± 600548 ± 350 Ratio (90 % CI) 0.93 (0.85-1.01) 0.93 (0.86-1.02) 0.89 (0.81-0.98)

10. Case study 2 Pharmacokinetic parameters, single dose, fasting state, metabolite TreatmentAUC 0-t (ng*h/ml) AUC 0-inf (ng*h/ml) C max (ng/ml) Test1461± 4601500± 518481 ±240 Reference1560± 5301580± 580498 ± 250 Ratio (90 % CI) 0.94 (0.88-1.03) 0.94 (0.89-0.99) 0.89 (0.78-1.02)

11. Case study 2 for safety reasons single dose study with 1 mg is accepted since linear pharmacokinetics, enantiospecific methods are not needed

12. Case study 3 Characteristics of drug Z bioavailability 80-90 % linear pharmacokinetics at doses 0.25- 10 mg multiple strengths (1 mg and 2 mg)

13. Case study 3 Enteric coated capsule single dose study with 2 mg capsule performed in fasting state

14. Case study 3 Pharmacokinetic parameters, single dose, fasting state TreatmentAUC 0-t (ng*h/ml) AUC 0-inf (ng*h/ml) C max (ng/ml) Test 3490±21503670±2230980±460 Reference 3670±20103800±19901020±480 Ratio (90 % CI) 102.5 (94.8-110.3) 102.6 (95.6-111.5) 104.3 (98.3-116.9)

15. Case study 3 Weaknesses of the documentation study in fed state is missing