Clinical mycophenolic acid monitoring in liver transplant recipients

Table 1 Pharmacokinetic data of mycophenolic acid in adult liver transplant recipients

Ref.	Year	Regimen	Time since LT	n	Method	AUC0-12h (mg.h /L)	Mean tmax (h)	Mean C0h (mg/L)	Mean Cmax (mg/L)
Jain et al[65]	2001	TAC + MMF	Days 6-30	8	HPLC	40.0 ± 30.9 (7.3-102.3)	1.8 ± 1.6		10.6 ± 7.5
Mardigyan et al[92]	2005	TAC + MMF	> 12 mo	14	EMIT	45 ± 22	0.5	2.1 ± 1.5	12.2 ± 75
Pisupati et al[60]	2005	TAC + MMF	< week 1	10	HPLC	50.8 ± 42.1	1.8 ± 1.2		9.1 ± 7.2
			Weeks 1-2			60.3 ± 38.5	1.8 ± 1.4		11.6 ± 6.7
			Weeks 3-6			118.0 ± 57.6	1.3 ± 0.7		36.7 ± 15.6
Brunet et al[11]	2006	TAC + MMF	Day 6	13	HPLC-UC	17.4 (13.2-39.7)	2	0.4	4.6
			Day 16	13		26.3 (13.1-45.8)	1.2	0.6	7.7
			Month 3	14		33.6 (15.1-54.6)	0.7	1.3	6.6
Chen et al[71]	2007	TAC + MMF	Day 7	38	HPLC	44.6 ± 16.50 (17.99-96.87)	1.42 ± 0.77		8.45 ± 4.77
			Day 14	34		50.54 ± 18.60 (22.78-98.73)	1.45 ± 0.81		11.29 ± 5.51
Chen et al[76]	2008	TAC + MMF	Days 7-14	48	EMIT	45.77 ± 18.69 (10.66-117.01)	1.94 ± 1.65	2.02 ± 1.57	11.76 ± 6.34
Kamar et al[93]	2009	TAC + MMF	Day 7	15	HPLC	36.8 ± 27
			Day 14	15		32.6 ± 11
			Day 30	15		36.7 ± 13
Beckebaum et al[94]	2009	TAC + MMF	Day 60 (14-230 d)	18	LC-MS/MS	55.9 (22.9-144.8)	0.5	3	14.2
		CsA + MMF	Day 70 (11-87 d)	12		52.2 (31.8-102.1)	1	2.5	15.3
Benichou et al[61]	2010	TAC + MMF	Day 12 (4-20 d)	26	EMIT	26.8 (21.8-39.7)
			Day 36 (24-90 d)	25		45.2 (26.0-57.0)

TAC: Tacrolimus; MMF: Mycophenolate mofetil; CsA: Cyclosporine A; HPLC: High-performance liquid chromatography; EMIT: Enzyme multiplied immunoassay technology.

Table 2 Limited sampling strategy for prediction of full mycophenolic acid area under the concentration-time curve in liver transplant recipients

Ref.	Method	Regimen	Patient population	No. of files (cases)	Sampling times investigated (h)	Suggested times of LSS (h)	Predicted AUC =	r2	LSS validation	Bias	Precision
Attard et al[78]	EMIT or	CsA or TAC	Pediatrics	41 files	0, 0.33, 0.67, 1.25, 2, 4, 6, 8	0, 0.33, 2	9.1 + 5.7*C0h + 1.1*C0.33h + 2.1*C2h	0.740	No	N/A	N/A
	HPLC-UV	+ MMF		(41 cases)		0, 0.67, 6	5.2 + 7.1*C0h + 1.1*C0.66h + 5.4*C6h	0.880	No	N/A	N/A
Chen et al[71]	HPLC	TAC + MMF	Adults	72 files	0.5, 1, 1.5, 2, 4, 6, 8, 10, 12	1, 2, 4	10.776 + 0.749*C1h + 1.604*C2h + 4.116*C4h	0.750	Validation	Yes	Yes
				(40 cases)		1, 2, 6	10.229 + 0.925*C1h + 1.750*C2h + 4.586*C6h	0.855	Group	Yes	Yes
						1, 2, 6, 8	5.503 + 0.919*C1h + 1.871*C2h + 3.176*C6h + 3.664*C8h	0.921		Yes	Yes
						1, 2, 4, 6	6.658 + 0.921*C1h + 1.573*C2h + 2.057*C4h + 3.543*C6h	0.899		Yes	Yes
Chen et al[76]	EMIT	TAC + MMF	Adults	48 files	0.5, 1, 1.5, 2, 4, 6, 8, 10, 12	1.5, 6	10.56 + 1.55C1.5h + 6.44C6h	0.859	Bootstrap	Yes	Yes
				(48 cases)		2, 4, 8	9.37 + 2.18C2h + 2.10C4h + 4.71C8h	0.901		Yes	Yes
						1, 2, 4, 8	4.46 + 0.81C1h + 1.78C2h + 2.51C4h + 4.94C8h	0.950		Yes	Yes
						1, 2, 4, 6	5.92 + 1.10C1h + 1.01C2h + 1.77C4h + 4.80C6h	0.927		Yes	Yes

LSS: Limited sampling strategy; MPA: Mycophenolic acid; AUC: Area under the concentration-time curve; EMIT: Enzyme multiplied immunoassay technology; HPLC: High-performance liquid chromatography; TAC: Tacrolimus; MMF: Mycophenolate mofetil; CsA: Cyclosporine A.

Table 3 Receiver operating characteristic analyses of mycophenolic acid exposure and mycophenolate mofetil-related side effects in liver transplant recipients

Ref.		Area under ROC curve	95%CI	Cut-off value	P value
Hao et al[31]	Side effects1
	MPA C0h	0.748	0.619-0.877	2 mg/L	0.001
	MPA AUC0-12h	0.695	0.559-0.831	40 mg.h/L	0.012
	Leukopenia
	MPA C0h	0.670	0.534-0.805	2 mg/L	0.026
Tredger et al[32]	Leukopenia
	MPA C0h	0.780	0.642-0.919	2.25 mg/L	0.003
	MMF dose	0.750	0.662-0.837		0.007
	Infection
	MPA C0h	0.634	0.499-0.770	2.85 mg/L	0.056

¹Side effects include leukopenia, diarrhea and infection. MMF: Mycophenolate mofetil; ROC: Receiver operating characteristic; MPA: Mycophenolic acid.