Case studies Saila Antila, PhD WHO consultant Training workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence, Kiev

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

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

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 ± ± ± 3.9 Reference187 ± ± ± 4.1 Ratio (90 % CI) 96.8 ( ) 92.3 ( ) 97.2 ( )

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 ± ± ± ± 48 Referenc e 190 ± ± ± ± 42 Ratio (90 % CI) 91.7 ( ) 80.1 ( ) ( ) ( )

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

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

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

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± ± ±340 Reference4670± ± ± 350 Ratio (90 % CI) 0.93 ( ) 0.93 ( ) 0.89 ( )

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± ± ±240 Reference1560± ± ± 250 Ratio (90 % CI) 0.94 ( ) 0.94 ( ) 0.89 ( )

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

Case study 3 Characteristics of drug Z bioavailability % linear pharmacokinetics at doses mg multiple strengths (1 mg and 2 mg)

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

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± ± ±460 Reference 3670± ± ±480 Ratio (90 % CI) ( ) ( ) ( )

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