Clinical pharmacology in Phases 2 to 4

1. Clinical pharmacology in Phases 2 to 4 • Phases 2 & 3 ̶ facilitates development • needed for regulatory dossier & SmPC • Phase 4 ̶ supports marketing

2. Core Phase 1 studies • FIH single dose – safety, tolerability and PK/PD • Repeated dose – safety, tolerability and PK/PD • Food effect • Male vs female • Elderly vs young • Bioequivalence of new formulations

3. Possible studies • ‘Thorough QT’ study • Absorption (distribution) metabolism elimination (ADME) • PK & PD in the target population • PK & PD in special patient groups • Mechanistic studies • Suitability/acceptability of formulations • Chronopharmacology • chronopharmacokinetics • chronopharmacodynamics

4. Repeated dose Purpose • tolerability more realistic than single dose • test if PK predictable from single dose data When/if needed • always, unless drug given intermittently • possible, but harder, to get data in a phase 2 study Design • dosing regimen must reflect expected clinical use • dose to steady-state • the longer the better: 5 – 28 days • PK profile on Day 1 and Daylast • include PD if you possibly can

5. Repeated dose Mean plasma concentrations of drug X (n=9 per dose)

6. Repeated dose Mean serum testosterone (baseline adjusted) versus time (n=9 per dose)

7. Food effect (oral drugs) Design • usually single-dose, in volunteers • overnight fast vs high fat breakfast (FDA) • glass of whole milk • 2 fried eggs • 2 bacon strips • 4 oz hash browns • toast & 20 g butter • simple PK profile

8. Food effect (oral drugs)

9. Male vs female Purpose • to test if PK + tolerability differ between men & women When needed • early in development – allows women into early studies, but… • teratology data must be available Design • usually single dose PK comparison

10. Elderly Rationale • main consumers of drugs • more heterogeneous than younger population • more adverse drug reactions Timing/design • PK/tolerability/PD study may be needed before clinical trials in elderly • use healthy elderly <80 y • frail elderly too high risk • single & repeated dose

11. Bioequivalence Purpose • to show that new dose form has same bioavailability as previously studied one When needed • for regulatory submission • often done during development, to ‘bridge’ to new formulation: eg solution→capsule→tablet→market image Design • detailed regulatory guidelines – little room for flexibility • FDA: test batch of ‘market image’ form must be at least 10% of a production run size

12. Absolute bioavailability Purpose • regulators (esp EU) like definitive PK parameters:CL, Vd, F all require IV dose • to explain poor bioavailability • pharmaceutical factors (eg dissolution, poor solubility) • property of molecule (first-pass extraction) When needed • as soon as poor bioavailability identified, to allow development of new formulations Design • single-dose, crossover, healthy volunteers • requires IV formulation & IV toxicology

13. Absolute bioavailability – microdose method obviates need for IV toxicology Design single-dose, healthy volunteers microdose = <100 µg or 1/100 of pharmacologically active dose conventional dose orally microdose IV at Tmax (eg 1.5 h) postdose microdose may be 14C labelled Accelerator Mass Spectrometry (AMS) allows tiny dose (‘light label’) of 14C

14. 14C-YF476, 15 μg iv, measured by AMS Mean concentration (ng/mL) YF476, 100 mg oral, measured by LCMS/MS Time (h) Absolute bioavailability of YF476. Mean (n=6; ±sd) scaled to 100 mg

15. Absorption, (Distribution), Metabolism, Elimination Purpose • confirm PK parameters (NB can’t show absolute bioavailability, unless 100% dose →urine) • show excretory pathways – renal, hepatic • get data on metabolites & biotransformation pathways When needed • as early as possible • may require extra toxicology • may (rarely) kill off drug

16. Absorption, (Distribution), Metabolism, Elimination Design radiolabelled drug – typically 1–2 MBq 14C total urine & faecal collection for 7 days PK profile Days 1–2 then daily blood samples total 14C analysis by liquid scintillation counting acceptable radiation exposure use of ‘light label’ – 8 kBq – requires AMS: feasible, but lab techniques too complex for routine use

17. Drug interactions Purpose • test if safety or efficacy of your drug (the victim)is likely to be affected by other drugs • test if safety and efficacy of other drugs is likely to be affected by your drug (the perpetrator) When needed • if interaction is probable, or likely to be clinically important, may be required before patients risk exposure in a clinical trial • otherwise, data required for regulatory submission

18. PK & PD in target population Purpose • link healthy subjects’ data to that in target disease When needed • helpful early in drug development, for dose decision • otherwise, required for regulatory submission Design • depends on drug type & target population • data may be available from Phase 2 studies • population PK invaluable

19. Special patient groups • children • renal failure • hepatic failure • others • if safety or efficacy likely to differ, eg cardiovascular disease

20. Children & adolescents Rationale • few drugs labelled for use in children, so • miss out on advances in medicines • at higher risk from medicines • drugs must be studied in children to determine safety & efficacy • immaturity can alter PK, organ response, & toxicity • (possible patent extension opportunities) Timing • for drugs mainly used in adults, after • pivotal proof of efficacy • after filing of adult dossier • after approval of adult dossier

21. Children Design • if disease mechanism is similar in adults and childreneg adolescents, suicide and SSRI • and a good PK - PD model in adults • then PK study in children plus safety study may be enough • otherwise may need some efficacy data too • studies are hard to do • ethics & consent • few children affected (they’re not like the elderly) • nervous clinicians

22. Mechanistic & biomarker studies Rationale • scientifically important • support efficacy claims • support safety claims • attract investment • comparative studies can support marketing

23. Chronopharmacology Rationale • circadian and other periodic influence PK response to drugs • some diseases show circadian and other rhythms • timing can affect PK & PD • evening dosing to prevent morning heart attack Design & timing • drug-specific • chronopharmacology is underinvestigated • drug development is difficult enough already

24. PK Absorption Distribution Metabolism Excretion PD Efficacy Toxicity Dosing regimen Commercial Dosing frequency Dose size Patient factors Age Disease Weight Con meds Genetics

25. Getting the dose too high • captopril • benoxaprofen • atenolol • cerivastatin • 1980–1999, 20% of drugs had postmarketing dose change • 79% of the changes were safety-motivated decreases • Cross J, et al. Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980–1999. Pharmacoepidemiol Drug Saf 2002;11:439–446. • Heerdink ER, Urquhart J & Leufkens HG. Changes in prescribed drug doses after market introduction. Pharmacoepidemiol Drug Saf 2002; 11: p. 447–453

26. What dose? • optimum dose = lowest dose producing a satisfactory response in most patients with acceptable safety • individualisation of dose as yet v poorly developed • need for positive results in Phase 3 encourages study of too high doses

27. How often to give the dose? • continuous drug effect not necessarily required • eg aminoglycosides: safer and just as efficacious when given once daily despite 90 min t1/2 • cimetidine as effective when bd as qid despite short t1/2 • continuous drug administration produces tolerance • nitrates

28. Summary • understanding the nature of drug response is essential • selecting the right dose is crucial but it’s tricky • correct selection of dosing regimen is difficult but can make all the difference for • efficacy • safety • commercial success • much of the ‘label’ is clin pharm – so lots of work to do • individual optimisation of dose (currently primitive) could make drugs more effective & safer