Table XIII. MMF exposure – effect studies in heart transplantation.

Results are expressed as mean±SD, unless otherwise specified

Ref	Immunosuppressants	Number of patients	Sampling periods	Exposure (analytical method)		Event (Number of episodes)		Comments
[132]	MMF, steady-state 1.1±0.4 g BID (13.6±4.9 mg/kg BID)	38 patients OHT 53±10 years	310±278 days	MPA AUC, fAUC, C0 (HPLC-UV) MPA AUC0-12 calculated from a 2-hour abbreviated AUC developed in renal transplant patients[216]		3 groups (ISHLT classification)		No significant differences in cyclosporine exposure
				AUC	42.8±14	Grade 0		Prednisone dose varying among the patients
				fAUC	0.81±0.25	n = 22 patients
				C0	1.20±0.58
				AUC	51.7±17.5	Grade 1		Small sample size (3 patients in the grade2/3 rejection group)
				fAUC	0.95±0.34	n = 13 patients
				C0	1.24±0.72
				AUC	26.1±6.6 (p < 0.05 vs grade 0 and 1)	Grade 2/3		Patients sampled at varying times throughout their post-transplantation course
				fAUC	0.49±011 (p < 0.05, vs grades 0 and 1)	n = 3 patients
				C0	0.65±0.15 (ns vs grades 0 and 1)
[163]	MMF, steady-state Increased to the maximal tolerated dose D = 2.1±0.9 g/day (1.0–4.0) Corticosteroids (50%)	26 patients 54±14 years (22–72)	3.0±1.7 years (1.0–7.8)	MPA and MPAG C0 (HPLC-UV) “Therapeutic” C0 levels: MPA > 2 mg/L Cyclosporine ≥ 175 μg/L Tacrolimus ≥ 10 μg/L		48 routine EMB at time of blood sampling (ISHLT) Grade 0, 46%; grade 1A/1B, 33%; grade 2, 8%; grade 3A, 4% MPA C0 vs overall incidence of rejection: ns
	Cyclosporine (42%)			n = 19 samples		Overall rejection ≈ 20%
	MMF D = 2.4±0.9 g/day			MPA C0 = 1.65±0.97		Cyclosporine C0 < 175 μg/L in 100% of patients
				MPAG C0 = 128.9±55.6
	Tacrolimus (58%)			n = 29 samples		Overall rejection ≈ 60% (significantly higher, p: N/R)
	MMF D = 1.8±0.8 g/day (p = 0.01)			MPA C0 = 2.86±2.07 (p = 0.02)		Tacrolimus C0 < 10 μg/L in 52% of patients
				MPAG C0 = 101.1±84.9 (ns)
[136]	MMF, steady-state D = 37.9±12.5 mg/kg = 1.207±0.302 g/m2	26 patients (16 children, 10 adults)	50% < 1 year 50% > 1 year	MPA and MPAG C0 (HPLC)		78 EMB (ISHLT classification)
				MPA C0 = 2.5±2.3		Grade < 2 (n = N/R)
	Cyclosporine or tacrolimus Corticosteroids	15±10 years (1 month – 33 years)		MPA C0 = 1.2±0.9 (p = 0.02)		Grade ≥ 2, (n = N/R) More frequent with MPA C0 ≥ 2.5 mg/L (p = 0.03)
[170]	MMF, 1.5 g BID (decreased based on clinical symptoms of toxicity)	20 patients	< 1 year (mean: 10.1 months)	MPA C0 (EMIT) Median: 1.51 (DF50 = 0.96–2.23)		147 EMB (ISHLT)
	Cyclosporine (possibly converted to tacrolimus)			Difference in cyclosporine and MPA C0 between categories of biopsies: ns		Grade 0, n = 54; grade 1A, n = 61; grade 2, n = 16, grade 3A, n = 16
	Prednisone			Median MPA C0: 1.76 (range: 0.496–7.65)		Patients without AR, n = 9
				Median MPA C0: 1.36 (range: 0.26–6.13); p = 0.015		Patients with AR, n = 11
[139]	MMF, 2 g/day D adjusted on C0: 2–4 mg/L	215 patients 36±14 yrs		MPA C0 (EMIT); 892 plasma samples (3 groups based on C0: < 2, 2–4, > 4, or 2 groups based on C0 < 2 and C0 ≥ 2, to compare the incidence of rejection)		Scheduled EMB Acute rejection if grade ≥ 3A (ISHLT)		50 patients had samples taken on more than one occasion
	Cyclosporine (89%) or tacrolimus (11%) D adjusted on C0 Prednisone (all)
	Rejectors: 2.8±0.8 g/day	Period I n = 104	< 6 months	No difference in mean C0 between patients with (C0 = 2.2±2.0 mg/L) and without (C0 = 2.3±1.7 mg/L) AR		No difference in AR incidence between the 3 C0 groups (p = 0.1): 7.8 to 14.9%
	Non rejectors: 2.8±0.7 g/day (ns)			Higher proportion of C0 < 2 in rejectors (n = 34/54) vs non rejectors (n = 194/401), p = 0.05
				Difference in cyclosporine or tacrolimus C0 between MPA C0 groups: ns Mean daily MMF dose to reach MPA C0 > 2, cyclosporine group vs tacrolimus group: ns When MPA C0 < 2, no difference on AR incidence in relation to therapeutic or subtherapeutic cyclosporine or tacrolimus C0 (14.4 vs 13.9%, ns) When MPA C0 > 2, AR incidence is significantly reduced if cyclosporine or tacrolimus C0 are therapeutic vs subtherapeutic (3.6 vs 15.4%, p = 0.002)
	Rejectors: 2.5±1.0 g/day	Period II n = 90	6–12 months	No difference in mean C0 between patients with (C0 = 2.0±1.5 mg/L) and without (C0 = 2.7±2.0 mg/L) AR		No difference in AR incidence between the 3 C0 groups (p = 0.15): 4.0 to 11.3%
	Non rejectors: 2.6±0.7 g/day (ns)			Higher proportion of C0 < 2 in rejectors (n = 9/14) vs non rejectors (n = 71/188), p = 0.05
	2.3±0.8 g/day 2.3±0.8 g/day (ns)	Period III n = 71	> 12 months	No difference in mean C0 between patients with (C0 = 2.4±2.0 mg/L) and without (C0 = 2.6±2.2 mg/L) AR		No difference in AR incidence between the 3 C0 groups (p = 0.13): 2.6 to 15.1%
				Comparable proportion of C0 < 2 in rejectors (n = 13/27) vs non rejectors (n = 98/208), p = 0.92
[129]	MMF Tacrolimus Prednisone (weaning at 6 months)	45 adults Primary OHT		MPA C0 (EMIT) Tacrolimus C0 (IMx)		EFFICACY Patient survival EMB (ARE, ISHLT classification)	TOXICITY GI toxicity Infections
	MMF D = 2 g/d (fixed) Tacrolimus D adjusted on C0	Phase I n = 15 51±11 years	696±62 days (606–790)	Mean MPA levels (Months 0–6)		Patient survival: 100%	GI toxicity: n = 6 (40%)
						Tacrolimus C0, patients with vs without AR: ns	Infections:
				3.6±0.4		0 ARE/patient, n = 5	Bacterial, n = 10 (66.7%) Fungal, n = 8 (53.3%) Viral, n = 9 (60.0%)
				2.2±0.4		1–2 ARE/patient n = 7 patients
				1.4±0.2		3 ARE/patient, n = 3
	MMF and tacrolimus D adjusted on C0	Phase II n = 30 54±9 yeras	436±88 days (175–562)	MPA C0 target: 2.5–4.5		27 patients: rejection-free 3 patients with AR had confounding factors	GI toxicity: n = 9 (30%) Infections: Bacterial, n = 17 (56.7%) Fungal, n = 5 (16.7%) Viral, n = 7 (23.3%)

AR: Acute rejection – ARE: Acute rejection episode – CF: Cystic fibrosis – D: Dose – f: Free fraction – EMB: Endomyocardial biopsy – GI: Gastro-intestinal – N/R: not reported.