Early Phase Clinical Trials in Patients with Hepatic or Renal Impairment: From Design to Data Analysis

EARLY PHASE CLINICAL TRIALS IN PATIENTS

WITH HEPATIC OR RENAL IMPAIRMENT:

FROM DESIGN TO DATA ANALYSIS

Nariné Baririan, Pharm.D

PK Expert

SAFETY & EFFICACY CLINICAL TRIAL SOLUTIONS SGS Life Science Services Biopharm Day Seminar – Antwerp, October 29, 2015

2 SGS LIFE SCIENCE SERVICES BIOPHARMA DAY – OCTOBER, 29 2015

CLINICAL PHARMACOLOGY TRIALS

ADME (Mass Balance)

First-in-Human (SAD and MAD Studies)

Healthy vs. Patient Population

Specific Populations

Hepatic Impairment

Renal Impairment

Age, Gender, Pediatrics, Genotype-phenotype, etc.

DDI

…


CP TRIALS IN RI PATIENTS: GUIDANCES



FDA and EMA guidances not always consistent

FDA guidance still in draft for 5 years

EMA guidance not enough detailed

Which guidance to follow?

- Case-by-case decision

- Good knowledge of drug properties

- In depth study design discussions

- Expertise

- Feasibility analysis

- Get advise from the authorities




CP TRIALS IN RI PATIENTS: DESIGN

Full or reduced design?

How to deal with low number of subjects?

Which matching strategy to choose?

Effect of dialysis on PK – to asses or not?

Which RI classification to use?

Single or multiple dosing?

Parent drug and/or metabolites?

Bound and/or unbound concentration of drug?

Dose adjustment in RI patients

Some key questions to be answered :




• Group matching

• One to one matching

• One to one matching with reuse of healthy volunteers data among RI

groups

Mandatory matching criteria = age, BMI, gender, ethnicity

Some matching criteria can be challenging for HVs




Effect of dialysis on PK – to asses or not?

• Drugs that are not likely to be administered

to dialyzed patients

• Dialysis procedure is unlikely to result in

significant elimination of drug

• Technical aspects of the dialysis


2000, Dialysis of Drugs; NPA

Curtis A. Johnson, PharmD

William D. Simmons, RPh


CP TRIALS IN RI PATIENTS: DESIGN / DATA

ANALYSIS

Effect of dialysis on PK – to asses or not? YES


Two treatment periods: IDTP and DTP

Venous blood samples during IDTP and blood from

arterio-venous sides of fistula during DTP

Drug concentration in dialysate

Drug free fraction

Total plasma proteins in arterial and venous sides during DTP

Hemodialysis parameters: QB, QUF…

IDTP: Inter-dialysis treatment period

DTP : Dialysis treatment period


CP TRIALS IN RI PATIENTS: DESIGN / DATA

ANALYSIS

Effect of dialysis on PK – to asses or not? YES


Calculated PK metrics:

- In DTP

Standard PK parameters (from venous side blood)

Special to dialysis PK parameters (E, QPL, CLD, CLUF, CLHD, AR)

- In IDTP

Standard PK parameters


CP TRIALS IN RI PATIENTS: DATA ANALYSIS


Dosage adjustment for RI patients

Obvious or partial effect?

Dose and/or dosing regimen adjustment?

General approach to dose adjustment with some conditions

Modeling & simulation is highly recommended

Extra caution is needed when developing a drug with NTI


CP TRIALS IN RI PATIENTS: DATA ANALYSIS

Decreased first-pass effect in severe RI (hepato-renal syndrome)

Differently affected metabolic enzymes activity

Differently affected transporters

Possible DDI

Differently altered plasma protein binding

Unbound concentration should be measured and interpreted

Altered PD response for some therapeutic agents

The influence of RI on drug PK should be correctly

interpreted

!


CP TRIALS IN HI PATIENTS: GUIDANCES



No recent review of both Guidances: FDA – 2003, EMA -2005

EMA guidance not enough detailed

EMA guidance very limited in statistical considerations

Which guidance to follow?

- Case-by-case decision

- Good knowledge of drug properties

- In depth study design discussions

- Expertise

- Feasibility analysis

- Get advise from the authorities




CP TRIALS IN HI PATIENTS: DESIGN


How to deal with low number of subjects?


Single or multiple dosing?

Parent drug and/or metabolites?

Bound and/or unbound concentration of drug?

Dosage adjustment in HI patients





Reduced PK study – for drugs not excessively (20-30%) metabolized or

excreted in bile - no advise from EMA and FDA guidances

- Moderate HI impaired and subjects with normal hepatic

function (≥8 per group)

- If a reduced PK study shows substantial effect in HI patients

a full PK study is highly recommended

Full PK study – Standard = Single dose, parallel groups, healthy males and

females and all degrees of HI (≥6 per group)




Dosage adjustment for HI patients


Obvious effect of HI on drug PK dose adjustment

No effect of HI on drug PK no dose adjustment

Partial effect of HI on drug PK dose adjustment in

concerned HI groups

Modeling & simulation is highly recommended

Extra caution is needed when developing a drug with NTI

No effect boundaries

(BE vs wider boundaries) !


CP TRIALS IN HI PATIENTS: DATA ANALYSIS

Differently altered drug PK in function of cirrhosis etiology

Possible DDI

Child-Pugh classification is not sensitive enough to distinguish

Child A from B

Impact of cirrhosis-related GI dysfunction on drug absorption

Altered biliary excretion

The influence of HI on drug PK should be correctly

interpreted

!


CP TRIALS IN HI PATIENTS: DATA ANALYSIS

The influence of HI on drug PK should be correctly

interpreted

Altered plasma protein binding

Unbound concentration should be measured and interpreted

Altered renal excretion (hepato-renal syndrome)

Use of serum CR is not a good approach to estimate the degree

of renal dysfunction

Altered PD response for some therapeutic agents

!


CP TRIALS IN HI/RI PATIENTS: CONCLUSIONS

At early stage of drug development studies in HI/RI special

populations are almost always required for drugs with systemic

absorption

Conclusions in HI/RI trials are very difficult, variable and often

not clear

Recommendations after Early Phase HI/RI full study should be

evidence-based, and ideally, confirmed by PK/PD study in

much larger patients population


CP TRIALS IN HI/RI PATIENTS: CONCLUSIONS

CROs role in conducting HI/RI trials :

State-of-the-art hospital-based unit(s) close collaborating with

big hepatology and nephrology units

Fast recruitment of patients

Expert investigators teams

Good scientific expertise with high quality in the design and

conduct

Scientific interpretation of results

Provide good communication and good management


Life Science Services Narine Baririan, Pharm.D

PK Expert

SGS Belgium NV Phone: +32 (0)15 27 32 45

Clinical Research Mobile: +32 (0)48 4 64 34 46

Generaal de Wittelaan 19A b5 E-mail : [email protected]

2800 Mechelen

Belgium Web : www.sgs.com/lifescience

THANK YOU FOR YOUR ATTENTION

+ 41 22 739 9548

+ 1 866 SGS 5003

+ 65 637 90 111

+ 33 1 53 78 18 79

+ 1 877 677 2667

+ 33 1 41 24 87 87


QUESTIONS ?


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Early Phase Clinical Trials in Patients with Hepatic or Renal Impairment: From Design to Data Analysis