Variability of mycophenolic acid elimination in the renal transplant recipients – population pharmacokinetic approach

Figures & data

Table 1. Characteristics of study patients.

Characteristics	Model building patients Median (range)	Model validation patients Median (range)
Number of patients	70	25
Number of observations	90	25
Gender (male/female)	48/22	16/9
Diabetes	15	4
Donor type (living/deceased)	49/21	20/5
MPA + tacrolimus	61	23
MPA + cyclosporine A	9	2
MPA + prednisolone > 10	30	9
MPA + omeprazole	36	14
MPA + bisoprolol	21	7
MPA + carvedilol	24	8
MPA + nifedipine	23	11
Body weight (kg)	75.33 (53–113)	75.16 (51–117)
Age (years)	42.97 (21–70)	43.53 (26–68)
Time after transplantation (months)	51.14 (1–204)	45.28 (5–96)
Total MPA dose (mg/day)	1028.57 (720–1440)	943.2 (540–1440)
MPA serum concentration (μg/mL)	3.61 (0.14–19.13)	4.06 (0.08–15.21)
Hemoglobin(g/L)	139.27 (97–186)	139.4 (114–173)
AST (UI/L)	23.87 (9–202)	23.26 (10–51)
ALT (UI/L)	31.48 (0.9–423)	27.63 (10–81.2)
Serum creatinine (μmol/L)	141.43 (66–307)	144.11 (86.9–261.9)
Creatinine clearance (mL/min)	67.71 (21.24–144.76)	64.61 (42.08–121.73)
Albumin (g/L)	42.11 (36–49)	42.36 (37–49)
Urea (mmol/L)	8.4 (2.8–19.7)	7.91 (3.4–15.7)
Le (G/L)	7.9 (3.7–16.6)	8.2 (2.9–12.3)

Note: MPA – mycophenolic acid; total MPA dose – total dose of mycophenolic acid; AST – aspartate transaminase; ALT – alanine transaminase; Le – leukocytes.

Table 2. The value of MOF in the base model, univariate models and the full model.

Clearance models	MOF	Difference in MOF	p Value**	Conclusion
BASE MODEL CL/F = θ1 * EXP(ETA(1))	307.523
UNIVARITE MODELS CL/F = θ1 * EXP(ETA(1)) + θ2 * TBW	307.520	0.003	>0.05	NS
CL/F = θ1 * EXP(ETA(1)) + θ3 * AGE	285.725	21.798	<0.05	YES
CL/F = θ1 * EXP(ETA(1)) θ4 * GENDER	307.523	0	>0.05	NS
CL/F = θ1 * EXP(ETA(1)) + θ5 * DD	287.576	19.947	<0.05	YES
CL/F = θ1 * EXP(ETA(1)) θ6 * CLCR	281.158	26.365	<0.05	YES
CL/F = θ1 * EXP(ETA(1)) θ7 * ALB	274.899	32.624	<0.05	YES
CL/F = θ1 * EXP(ETA(1)) θ8 * TIME tx	307.324	0.199	>0.05	NS
CL/F = θ1 * EXP(ETA(1)) θ9 * STATUS don	284.684	22.839	<0.05	YES
CL/F = θ1 * EXP(ETA(1)) θ10 * GENDER don	300.516	7.007	<0.05	YES
CL/F = θ1 * EXP(ETA(1)) θ11 * AST	306.049	1.474	>0.05	NS
CL/F = θ1 * EXP(ETA(1)) θ12 * ALT	305.974	1.549	>0.05	NS
CL/F = θ1 * EXP(ETA(1)) θ13 * OME	307.523	0	>0.05	NS
CL/F = θ1 * EXP(ETA(1)) θ14 * NIF	283.482	24.041	<0.05	YES
CL/F = θ1 * EXP(ETA(1)) θ15 * CYC dose	307.422	0.101	>0.05	NS
CL/F = θ1 * EXP(ETA(1)) θ16 * TAC dose	292.045	15.478	<0.05	YES
CL/F = θ1 * EXP(ETA(1)) θ17 * PRE dose	307.523	0	>0.05	NS
FULL MODEL CL/F = θ1 * EXP(ETA(1)) + θ3 * AGE + θ5 * DD + θ6 * CLCR θ7  * ALB θ9 * STATUS don θ10 * GENDER don θ14 * NIF θ16 * TAC dose	261.383

Notes: CL/F – apparent oral clearance (l h⁻¹); θ₁ typical value of CL; ETA(1) interindividual variability in CL; θ₂–θ₁₇ slopes of the covariate effects; TBW – total body weight (kg); GENDER takes the value 1 for male and 0 for female; DD – total daily dose of mycophenolic acid (mg day⁻¹); CL_CR – creatinine clearance (l h⁻¹); ALB – serum albumin; TIME tx – time after transplantation; STATUS don takes the value 1 for living donor and 0 for deceased donor; GENDER don takes the value 1 for male and 0 for female; AST – aspartate transaminase; ALT – alanine transaminase; OME and NIF – co-medication with omeprazole and nifedipine, takes the value 1 if the patient received co-medication and 0 otherwise; CYC dose – cyclosporine A dose takes the value 1 if ≥ 2 (mg day⁻¹) or 0 if < 2 (mg day⁻¹); TAC dose – tacrolimus dose takes the value 1 if > 3 (mg day⁻¹) or 0 if ≤ 3 (mg day⁻¹); PRE dose – prednisolone dose takes the value 1 if ≥ 10 (mg day⁻¹) and 0 if < 10 (mg day⁻¹); NS – Not significant.

*Indicates calculation operation-multiplication. **Suggest statistical significance.

Table 3. Parameter estimates for the final model.

Parameters	Estimated value (SE)
Apparent oral clearance (l h^−1) CL/F	0.741 (0.037)
Apparent volume of distribution (l) Vd/F	0.653 (0.073)
Apparent volume of distribution in steady-state  (l) VSS/F	801 (174.13)
Intercompartment clearance (l h^−1) Q/F	52.1 (4.102)
Absorption rate constant (h^−1) Ka	4.07 (0.42)
Lag time (h)	0.21 (0.03)
Interindividual variance Ω
CL/F	0.061 (0.013)
Vd/F	0.059 (0.017)
VSS/F	154.04 (23.34)
Q/F	4.67 (1.46)
Ka	2.08 (0.1)
Lag time	0.12 (0.024)
Residual variance σ^2	0.123 (0.023)

Note: SE – standard error.

Figure 1. (a) Scatter-plots of predicted concentrations (PRED) and individual predicted concentrations (IPRED) versus observed concentrations (DV) for mycophenolic acid by the final model of index set. (b) Scatter-plots of PRED and IPRED versus DV for mycophenolic acid by the final model of validation set.

Figure 2. (a) Scatter-plot of weighted residuals (WRES) versus predicted concentrations (PRED) for mycophenolic acid by the final model of index set. (b) Scatter-plot of WRES versus PRED for mycophenolic acid by the final model of validation set.

Table 4. Prediction errors of final model established in validation set.

Error	Final model
Mean prediction error (MPE)	0.1172 (−0.8522 to 1.0866)
Root mean squared prediction  error (RMSE)	2.4256 (1.6096–3.0293)