Table 1. Population PK parameters

COMBACTE / STAT-Net is supported by IMI/EU and EFPIA

Figure 1. Examples

of concentration-

time profiles

Figure 3. VPC’s,

stratified on

dosing time

Figure 2.

Diagnostic plots

Highly variable absorption of clavulanic acid during the day:

a population pharmacokinetic analysis

f.develde@erasmusmc.nl

INTRODUCTION

Re-used data of trial 25000/360 (Smith-Kline Beecham, 1994):

• 29 healthy male volunteers (age 33 ± 7 years, height 179 ± 6 cm, weight 78 ± 9,

BMI 24 ± 2 kg/m2).

• amoxicillin/clavulanic acid tablets on 2 days (randomized order, 1 week apart) at

the start of a standard meal with 200ml water:

1. twice-daily (BID: 8h and 2h) 875/125mg (n=14) or 500/125mg (n=15).

2. three-times daily (TID: 8h, 16h, 24h) 500/125mg (n=14) or 250/125mg (n=15).

• 1479 blood samples (145 concentration-time profiles): 0,0.5,1,1.5,2,2.5,3,4,

6,8,10,12 h (TID ≤8h), measured with HPLC-UV.

Method: WinNonLin (version 7.0).

Results: Median Cmax was 2.21 mg/L (0.21-4.35) and median AUC0-8 4.99 mg*h/L

(0.44-8.31). In 40/58 daily concentration-time profiles, Cmax and AUC0-8 of the

morning dose were higher than later doses. Examples of individual concentration-

time profiles are displayed in figure 1.

• Clavulanic acid absorption in healthy volunteers is highly

variable.

• Bioavailability and absorption rate decrease over the day.

• The consequences of the variable concentrations (such as

under-dosing) should be further studied for multiple day dosing.

• Studies on the PD target are needed.

POPULATION PK ANALYSIS

CONCLUSIONS

DATA

Figure 4. %fT>Ct vs Ct for 125 mg BID and 125 mg TID

• Clavulanic acid is a beta-lactamase inhibitor used in combination with beta-

lactam antibiotics to target beta-lactamase-producing strains.

• Several non-compartmental PK studies showed highly variable PK for oral

clavulanic acid [1,2], but a population PK model is not available in the literature.

• The PD target of clavulanic acid is still unknown.

Vd: volume of distribution

CL: clearance

F: bioavailability

Ka: first-order absorption rate constant

RSE: relative standard error

CV: coefficient of variation

P25-1-8

15th IATDMCT 2017

Methods:

• Nonlinear mixed effect modelling: NONMEM version 7.2 (FOCE+I).

• Model selection criteria: decrease in objective function value, diagnostic plots and

visual predictive checks (VPC’s).

• Non-parametric bootstrap method: to obtain the 95% CI of each parameter.

Results:

• Clavulanic acid data were best described by a model with a lag time and first-order

absorption, 1 distribution compartment and first-order elimination (table 1).

• Dosing time was proportionally correlated with F and Ka.

• The diagnostic plots and VPC’s (figure 2+3) indicate a good predictive performance.

Table 2. fAUC0-24 distribution for 125 mg BID and 125 mg TID

REFERENCES[1] Nilsson-Ehle (1985), 16(4): 491-8.

[2] Vree (2003), 51(2): 373-8.

[3] GSK (2015), SPC Augmentin.

[4] De la Pena (1999), 37(2): 63-75.

[5] EUCAST (2017), breakpoint

tables.

NON-COMPARTMENTAL PK ANALYSIS

MONTE CARLO SIMULATIONSMethods:

• 5000 Monte Carlo simulations with clavulanic acid 125 mg BID and 125 mg TID.

• For each simulated concentration-time profile, both %fT>Ct for Ct of 0.015–64

mg/L and fAUC0-24 were calculated.

• Unbound concentration was calculated from the total concentration using a fixed

value for protein binding of 25% [3,4].

F. de Velde, B.C.M. de Winter, B.C.P. Koch, T. van Gelder, J.W. Mouton

Erasmus University Medical Center, Rotterdam, The Netherlands.

On behalf of COMBACTE consortium

Parameter Estimate RSE (%) 95% CI

Fixed effects

Vd/F (L) 33.0 3.8 30.3 – 35.6

CL/F (L/h) 24.6 3.8 22.6 – 26.6

F (-) 1 (fixed) - -

Ka (h-1) 3.99 14.1 3.07 – 5.20

Lag time (h) 0.447 1.3 0.436 – 0.456

Between-Subject-Variability (BSV)

Vd (%CV) 23.9 23.2 12.9 – 33.3

CL (%CV) 26.7 17.1 17.8 – 34.8

Ka (%CV) 52.8 15.8 34.4 – 67.8

Between-Occasion-Variability (BOV)

Ka (%CV) 48.5 12.8 37.8 – 60.2

F (%CV) 28.2 21.4 16.7 – 38.6

Parameter Estimate RSE (%) 95% CI

Covariate dosing time: proportional effect on Ka

8:00h 1 (fixed) - -

16:00h 0.903 9.9 0.737 – 1.08

20:00h 0.610 15.1 0.442 – 0.801

24:00h 0.636 14.8 0.476 – 0.843

Covariate dosing time: proportional effect on F

8:00h 1 (fixed) - -

16:00h 0.873 5.6 0.765 – 0.949

20:00h 0.799 7.4 0.688 – 0.904

24:00h 0.801 8.8 0.663 – 0.944

Residual unexplained variability (RUV)

Additive (mg/L) 0.0533 8.2 0.0450 – 0.0625

Proportional 0.142 8.2 0.119 – 0.165

0 1 2 3 4 50

1

2

3

4

5

Population predicted concentration (mg/L)

Ob

serv

ed

co

ncen

trati

on

(m

g/L

)

0 1 2 3 4 50

1

2

3

4

5

Individual predicted concentration (mg/L)O

bserv

ed

co

ncen

trati

on

(m

g/L

)

Percentiles of fAUC0-24 distribution

Min 0.01 0.025 0.05 0.50 0.95 0.975 0.99 Max

125 mg BID 2.10 3.17 3.61 4.07 6.94 12.2 13.7 15.4 28.0

125 mg TID 3.43 4.86 5.56 6.15 10.4 17.5 19.2 21.2 36.1

OBJECTIVES• Develope a population PK model to explore the variability of clavulanic acid

exposure after oral administration of amoxicillin/clavulanic acid.

• Determine target attainment using Monte Carlo simulations for both fAUC and

%fT>Ct (% of dosing interval that unbound concentration exceeds a threshold).

Results (figure 4 and table 2):

For 97.5% of the population:

• fAUC0-24 was 3.61 mg*h/L (125 mg BID) and 5.56 mg*h/L (125 mg TID)

• %fT>Ct at 0.5 mg/L was 8.33% (125 mg BID) and 15.2% (125 mg TID)

• %fT>Ct at 1 mg/L was 0% (both regimens).

• 46% (125 mg BID) and 53% (125 mg TID) of the population attained 2 mg/L (fixed

concentration used in current EUCAST guideline [5]), but the average %fT>Ct at 2

mg/L was low: 2.09% (125 mg BID) and 3.05% (125 mg TID).

Circles: observations.

Lines: 95th, 50th, 5th percentile of observations.

Areas: 95%CI of corresponding percentiles of predictions.

CONFLICTS OF INTERESTJWM has received research funding from IMI, EU, ZON-MW, Adenium, Astra-Zeneca,

Basilea, Eumedica, Cubist, Merck & Co, Pfizer, Polyphor, Roche, Shionogi, Thermo-

Fisher, Wockhardt, Astellas, Gilead and Pfizer. Other authors: none to declare.