Vol. 36, Special Issue, S 3 S 18 (2015) PK Phase I Introduction to Pharmacokinetic Analysis Focus on Phase I Study 1 2 Kazuro Ikawa 1 and Jun Tanaka 2

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1 Vol. 36, Special Issue, S 3 S 18 (2015) PK Phase I Introduction to Pharmacokinetic Analysis Focus on Phase I Study 1 2 Kazuro Ikawa 1 and Jun Tanaka Department of Clinical Pharmacotherapy, Hiroshima University 2 Chugai Pharmaceutical Co., Ltd. ikawak@hiroshima-u.ac.jp We describe fundamental knowledge of pharmacokinetics analysis for phase I trials, particularly focusing on basic parameters (such as bioavailability, volume of distribution, fraction unbound, clearance), estimation and analysis methods (such as compartmental and non-compartmental), points to consider (such as steady state and dose proportionality). The NCA is an abbreviation for Non Compartmental Analysis, and the meaning is pharmacokinetic analysis without pharmacokinetic model. There is something that we should consider in NCA such as AUC calculation method, handling method of not detectable concentrations, point selection for λ z calculation, and selection of sampling time. Steady state occurs when the overall intake of a drug is equilibrium with its elimination. At steady state the mean plasma concentrations of the drug are similar by any dosing interval. In practice, it is generally considered that steady state is reached when a time of 5 times the half-life for a drug. For the dose proportionality, the measures of exposure, such as maximal blood concentration (C max), area under the curve from 0 to infinity (AUC), are proportional to the dose. The three methods, Analysis of variance of the PK response, normalized by dose, linear regression and power model, are used to assess dose proportionality. Key words: volume of distribution, clearance, compartmental analysis, non compartmental analysis, steady state, dose proportionality. 1. Pharmacokinetics PK Pharmacokinetics PK

2 S 4 absorption distribution metabolism excretionpk 5 PK PK 1 bioavailability: F D 0 1 F D 2 volume of distribution: Vd V A C A = Vd C Vd 3 L Vd 36 L 1 V 1 1 Vd β 2 Vd ss 3 fraction unbound in blood: fub fub α clearance: CL 2 1. V 1, Vd β, Vd ss

3 PK Phase I S 5 2. CL [L/h] Q [L/h] Ca Cv E = (Ca Cv)/Ca CL[L/h] = Q[L/h] E 5 cumulative amount of drug excreted in urine: Ae Ae = / Ae = % = 70 % + 30 % PK PK area under drug concentration-time curve: AUC mean residence time: MRT C max t max C min t 1/2 3. PK PK 3 PK PK AUCC max C min t max Vd ss MRT t 1/2

4 S 6 3. PK 4. V 1, Vd β, Vd ss PK/PD 4 AUC MRT 5 6 PK C X dx/dt[mg/h] = CL[L/h] C [mg/l] 5 t 1/2 6 Phase I PK Ka 0 7 R

5 PK Phase I S compartment model bolus 7. 1 PK

6 S PK 9. 2 PK PK 4. NCA Non Compartmental Analysis 4.1 NCA NCA Non Compartmental Analysis Compartmental Analysis

7 PK Phase I S 9 NCA NCA NCA, 2001 AUCC max C min t max Vd ss MRT t 1/2 NCA, 2012 Ae t, Ae τ, Ae, U max U τ AUC t, AUC τ, AUC, C max C τ NCA AUC λ z AUC t AUC etc AUC t AUC NCA Phoenix/WinNonlin Pharsight SAS SAS Institute Inc.

8 S AUC NCA AUC Linear trapezoidal method 11 Log-linear trapezoidal method 12 AUC t = AUC t = nx i=2 nx i=2 (C i + C i 1) (t i t i 1) 2 (C i + C i 1) (ti ti 1) (lnc i lnc i 1) C i i t i i n

9 PK Phase I S AUC 1 t max t max Linear Up Log Down t max I NCA AUC AUC λ z 2 13 AUC AUC AUC = AUC t + Ct ˆλ z λ z AUC AUC = AUC t + Ĉt ˆλ z C t Ĉt ˆλ z

10 S AUC BLQ AUC AUC 0 AUC AUC 14 AUC 0 AUC 0 AUC 0 0 AUC AUC 15 AUC t AUC AUC, 2012 AUC t AUC 80 % 72 1 (AUC t /AUC ) > 0.2 AUC AUC 4.3 λ z λ z NCA 1 λ z λ z 16 t 1/2, AUC WinNonlin BLQ 3 C max t max

11 PK Phase I S AUC BLQ 3 λ z λ z C max λ z C max C max λ z λ z 16. λ z 4.4 NCA C max, t max NCA 1 C max, t max C max, t max

12 S 14 t max C max, t max t max C max, t max t max 4.5 NCA 1 BE BE 2 2, 2012 BE t max 90 % 90 % log(0.80) log(1.25) AUC t C max C max AUC AUC, t max, MRT, k el t max AUC C max AUC C max , 2001

13 PK Phase I S 15 C n(t) = C 0 1 e n k el τ 1 e k el τ e k el t C ss(t) = C e k el τ e k el t = 1 e n k el τ 1 «t 1 t 1/2 2 n k el τ t 1/2 C 0 C n(t) n t C ss(t) t 5 SAP 5 = «= AUC, C max, C min C av C max C min C max C min AUC τ C av AUC AUC τ 17 R (AUC) = AUC (day 1) /AUC τ(day 1) R (Cav ) = C av(day X) = AUC (day 1) /τ C av(day 1) AUC τ(day 1) /τ R (AUC) = AUC τ(day X) /AUC τ(day 1) R (Cmax) = C max(day X) /C max(day 1)

14 S AUC AI (AUC) = AUC τ(day X) /AUC (day 1) day X τ AUC (day 1) AUC AUC (day X) AUC AUC τ(day 1) AUC τ AUC τ(day X) AUC τ C max(day 1) C max C max(day X) C max C av(day 1) C av C av(day X) C av 6. C max, AUC AUC C max MRT C max Dose AUC Dose CL, V d, K a 2 3 C max, AUC 2

15 PK Phase I S AUC C max AUC C max 18 AUC i = α + β Dose i +ε i AUC i i AUC Dose i i ε i i α = 0 AUC = β Dose H 0 : α = 0 AUC i = α + β Dose i +ε i H 0 : α = 0 AUC i i AUC Dose i i ε i i AUC AUC Dose AUC H 0 : AUC dose 1 Dose1 = AUC dose 2 Dose2 AUC dose X DoseX AUC = AUC dose 3 Dose3 AUC = α Dose β β = 1 AUC = α Dose

16 S 18 H 0 : β = 1 log(auc i) = log(α) + β log(dose i) + ε i AUC = α Dose β log(auc i) = log(α) + β log(dose i) + ε i H 0 : β = 1 AUC i i AUC Dose i i ε i i (2010). 4.. (2001). (2012). (2013). 2.. Malcolm Rowland and Thomas N. Tozer. (2012). Clinical pharmacokinetics and pharmacodynamics: concepts and applications (4th edition). Lippincott Williams & Wilkins (Pennsylvania, USA).,,,, (2007) magazine/rinsho yakubutsu/fuhyo/ Michael E. Winter (2009). Basic clinical pharmacokinetics (5th edition). Lippincott Williams & Wilkins (Pennsylvania, USA). (2003)..., (2008)... (2002). 2..

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