Table IX. Tacrolimus exposure indices in cohort studies.

Results are expressed as mean±SD (range), unless otherwise specified

Ref	Number of patients	Post-transplantperiod	Tacrolimus dose	Co-administered Immunosup-pressant	Assay	Measured AUC	C0 (μg/L)	Cmax (μg/L)	tmax (h)	Others
HEART TRANSPLANTATION
[102]	14 adults 55.5 years (23–61)	< 6 months	First D = 0.03–0.40 mg/kg (median: 0.052 mg/kg)	ATG AZA Prednisone	MEIA – IMx	Non-compartmental PK analysis using Pharm-NCA computer program; AUC Trap; median (range) PK profiles after the first dose of tacrolimus
						AUC0-12 = 155.6 (103.5–728.7) AUC0-∞ = 285.3 (121.8–1540.0)	--	23.0 (10.7–84.4)	2 (1–4)	Cmin = 8.3 (< 5–54.1)
						Best correlation: C12-AUC: C12 = 0.0371 x AUC0-∞ – 2.1; r2 = 0.98 (p<0.001)
[100]	11 adults OHT		First D up to 0.15 mg/kg BID D adjusted on C0 < 15 μg/L	N/R		Non-compartmental PK analysis using TOPFIT v2.0; tmax: median (range)
		Profile 1 (day 1) NG tube	D = 0.053±0.031 mg/kg (0.026–0.143) CV = 59%		ELISA	AUC0-∞ = 191.8±137.1 (32.9–422.2)	--	23.6±22.4 (1.3–76.6)	2.84 (2–9.5)	--
						CV = 72% – n = 7		CV = 95% – n = 10	n = 10
					HPLC- MS/MS	AUC0-∞ = 141.9±93.6 (41.6–254.9)	--	20.8±15.9 (2.1–49.4)	2.75 (1.5–9.5)	--
						CV = 66% – n = 5		CV = 77% – n = 10	n = 10
		Profile 2 (last day) Hard capsules	D = 0.076±0.069 mg/kg (0.013–0.250) CV = 91%		ELISA	AUC0-∞ = 257.4±76.3 (144.8–442.7)	--	34.2±18.2 (19.0–84.7)	1.96 (0–4)	--
						CV = 30% – n = 10		CV = 53% – n = 10	n = 10
					HPLC- MS/MS	AUC0-∞ = 211.1±77.2 (104.2–362.9)	--	33.1±14.8 (13.3–66.6)	1.5 (1–8)	--
						CV = 37% – n = 10		CV = 45% – n = 10	n = 10
[103]	25 adults 47±10 years	Immediate post-transplantation period		Induction: ATG/OKT3	HPLC-MS/MS	Non-compartmental analysis using computer program PC Modfit v/6; AUC0-12 Trap
	n: N/R		D = 0.075 mg/kg/day
			First dose			78.1±59.0	--	14.7±7.8	2.1±1.7	--
			Steady-state			186±68.7		26.6±9.5	1.9±1.2
	n: N/R		D = 0.15 mg/kg/day
			First dose			142±116	--	24.5±13.7	1.9±1.2	--
			Steady-state			198±73.1		29.9±14.5	1.8±0.6
						r2 Cmin – AUC0-12: first D = 0.86; steady-state = 0.79
[115]	19 adults 46 years (28–48) OHT		D = 0.06 mg/kg/day (0.04–0.08) D adjusted on C0 = 5–20 μg/L	ATG AZA Prednisone	MEIA – IMx	2-compartment open model using P-Pharm popPK software
		PK1 (day 10)				--	12.5	--	--	--
		PK2 (month 2)				--	15.0	--	--	--
[111]	8 adults 45–60 years	4 to 16 months (mean: 10.6)	D = 0.02–0.1 mg/kg/day D adjusted on C0 = 5–12 μg/L	MMF Prednisone	MEIA II– IMx	Non-compartmental PK analysis using PK Calc software; AUC Trap; Mean (range)
						AUC0-12 = 151.7 (129.2–174.2) AUC0-∞ = 317.5 (189.2–445.7)	7.9 (6.0–9.7)	22.9 (18.3–27.5)	2.2 (1.5–2.9)	C12 = 7.6 (6.2–9.0) (vs C0: ns)
						r2 AUC0-12: C0, C1, C2, C3 = 0.09 to 0.26 (ns) C4, C5, C6, C7, C8 = 0.53 to 0.64 (p < 0.05) C9, C10, C11, C12 = 0.70 to 0.80 (p < 0.01)
[109]	22 adults 55±8 years (36–64) OHT	< Year 1	D = 0.3 mg/kg/day D adjusted on C0 = 10–20 μg/L Steady-state	MMF or AZA Steroids	MEIA – IMx	Non-compartmental PK analysis using MOMENT software (n = 25 PK profiles); AUC Trap
						AUC0-12 = 236.3±88.6 (81.5–419.8) AUC0-4 = 93.5±40.8 (35.9–180.9)	14.8±5.7 (3.9–25.9)	30.5±13.8 (10.3–57.8)	2.3±1.5 (0.5–6.0)	Cav = 19.7±7.4 (6.8–35.0)
						r2 AUC0-12: C0 = 0.80 C1 = 0.40 C2 = 0.81 C4 = 0.90 C12 = 0.89	r2 AUC0-4: C0, C1 = 0.70 C2 = 0.96 C4 = 0.73	Sparse sampling algorithms for AUC0-12: 3.75 + 5.52*C0 + 6.97*C4 – r2 = 0.95 0.98 + 4.17*C0 + 2.29*C2 + 5.3*C4 – r2 = 0.97
[104]	13 patients		D adjusted on C0 = 10–15 μg/L	ATG	N/R	Non-compartmental PK analysis performed using WinNonlin; AUC Trap
						AUC/D: (μg.h/L)/mg tacrolimus
		First dose	D = 0.077±0.011 mg/kg BID			AUC0-∞ = 186.7±96.6 CV = 52% AUC0-∞/D = 46.0±24.3 r2 AUC0-∞: C0.5 = 0.020; p = 0.66 C1 = 0.143; p = 0.226 C2, C3, C4, C6, C8, C10 = 0.764 to 0.88; p < 0.05 C12 = 0.895; p < 0.05	--	--	--	--
		First month Steady-state	D = 0.068±0.047 mg/kg BID			AUC0-12 = 202.6±61.3 CV = 30% AUC0-12/D = 69.0±43.9 r2 AUC0-12: C0 = 0.841; p < 0.05 C1 = 0.469; p = 0.014 C0.5, C2, C3, C10, C12 = 0.640 to 0.822; p < 0.05 C4, C6, C8 = 0.902 to 0.976; p < 0.05	--	--	--	--
[105]	23 patients 38 years (18–56)		D = 0.10 mg/kg/day D adjusted on C0 = 10–20 μg/L	N/R	MEIA – IMx	Non-compartmental PK analysis
		First dose				AUC0-12 = 116.3±58.9 Best r2 C4-AUC = 0.93	--	18.8±7.7	2.1±1.4	C12 = 5.8±2.7
		Day 3				AUC0-12 = 149.7±63.2 Best r2 C4-AUC = 0.92	--	23.7±10.4	2.2±1.3	C12 = 10.6±3.8
		Day 7				AUC0-12 = 216.6±89. 4 Best r2 C4-AUC = 0.95	--	32.4±11.5	1.9±0.8	C12 = 17.7±6.4
LUNG TRANSPLANTATION
[117]	20 patients		D adjusted on C0 = 7–12 μg/L	Patients converted from cyclospsorine to tacrolimus (rescue therapy)	N/R	Non-compartmental PK analysis
	8 CF	326 days (120–689)	7.9±2.8 mg/day (0.16±0.06 mg/kg/day)			--	10.3±2.6	--	--	--
	12 non-CF	436 days (155–714)	6.4±3.7 mg/day (p = 0.14) 0.11±0.06 mg/kg/day (p = 0.08)			--	10.7±1.6 (ns)	--	--	--
[114]	16 adults (5 CF) 45.5±3.4 years	98±19 wks	D = 3.6±2.5 mg BID (0.25–7.0) D adjusted on C0 = 5–15 μg/L	N/R	HPLC- MS/MS	Non-compartmental PK analysis (n = 22 profiles)
						AUC0-8 = 115.8±45.2 (41.0–212.3)	10.5±5.7 (3.4–30.4)	21.6±11.8 (5.9–50.0)	2.3±1.3 (0.0–5.0)	C2 = 19.1±11.7 (4.6–50.0)
						AUC0-4 = 67.9±31.1 (20.7–146.9)
						r2 C2-AUC0-8 = 0.50; r2 C4-AUC0-8 = 0.53
HEART AND LUNG TRANSPLANTATION
[110]	22 adults		D adjusted on C0 = 8–12 μg/L Steady-state	Low-dose corticoids	MEIA – IMx	Non-compartmental PK analysis – 3 full PK profiles/patient within 1 week; AUC trap; Median (range)
						AUC/D: (h.μg/L)/mg tacrolimus	C0/D: (μg/L)/mg tacrolimus	Cmax/D: (μg/L)/mg tacrolimus
	11 CF 30 years (21–43)	36.1 months	D = 12 mg/day (5–25)	AZA (n = 5) or MMF (n =2)		AUC0-12	C0	Cmax	tmax	C3 V1: 16.2 (11.4–30.5) V2: 21.6 (10.1–33.0) V3: 16.4 (6.5–26.0)
						V1: 170 (140–260)	V1: 8.2 (6.0–14.0)	V1: 23.4 (16.6–64.8)	V1: 1.5 (0.5–6.0)
						V2: 180 (110–310)	V2: 9.2 (4.7–13.2)	V2: 25.6 (15.6–65.7)	V2: 1.5 (1.0–8.0)
						V3: 160 (100–270)	V3: 8.5 (5.2–13.2)	V3: 23.4 (10.6–76.8)	V3: 1.5 (0.5–5.0)
						AUC0-12/D	C0/D	Cmax/D
						V1: 14 (8–34)	V1: 0.7 (0.5–2.3)	V1: 2.6 (1.2–4.7)
						V2: 17 (8–33)	V2: 0.7 (0.4–1.7)	V2: 3.2 (1.1–3.9)
						V3: 12 (9–32)	V3: 0.7 (0.3–1.7)	V3: 2.2 (1.2–3.4)
						AUC0-4				C3/D V1: 1.5 (0.7–3.3) V2: 1.7 (0.6–3.6) V3: 1.4 (0.9–3.3)
						V1: 80 (60–150)
						V2: 100 (50–170)
						V3: 70 (40–180)
						AUC0-4/D
						V1: 8 (4–6)
						V2: 10 (3–13)
						V3: 7 (4–14)
						AUC/D smaller by about 50% in CF patients: AUC0-12/D, p < 0.004; AUC0-4/D, p < 0.001
						r2 AUC0-12: C0.5 = 0.35 C0, C1, C1.5 = 0.53 to 0.58 C2, C2.5, C4 = 0.71 to 0.80 C3 = 0.86		r2 AUC0-4: C0 = 0.34 C0.5, C4 = 0.46–0.53 C1, C1.5, C3 = 0.79 to 0.83 C2, C2.5 = 0.89–0.90
	11 non-CF 51 years (31–56) p < 0.01	32.6 months p = 0.97	D = 6.1 mg/day (3–10) p = 0.008	AZA (n = 5)		AUC0-12	C0	Cmax:	tmax	C3 V1: 19.4 (12.5–25.0) V2: 16.3 (9.4–26.9) V3: 16.9 (11.0–26.4)
						V1: 210 (120–270)	V1: 9.9 (6.4–14)	V1: 32.8 (15.5–57.8)	V1: 1.5 (1.0–4.0)
						V2: 180 (80–270)	V2: 10.9 (5.0–17)	V2: 29.1 (11.1–68.0)	V2: 1.0 (0.5–5.0)
						V3: 170 (80–240)	V3: 9.8 (5.4–13.7)	V3: 30.6 (11.6–43.5)	V3: 1.5 (1.0–3.0)
						AUC0-12/D	C0/D	Cmax/D:
						V1: 31 (17–71)	V1: 1.8 (1.0–2.4)	V1: 5.5 (2.4–15.2)
						V2: 33 (12–72)	V2: 1.9 (0.7–3.1)	V2: 6.5 (1.4–14.1)
						V3: 30 (12.69)	V3: 2.0 (0.8–3.4)	V3: 5.6 (1.6–4.5)
						AUC0-4				C3/D V1: 3.5 (1.9–8.3) V2: 3.6 (1.2–7.2) V3: 2.8 (1.6–6.3)
						V1: 110 (60–140)
						V2: 80 (40–150)
						V3: 90 (40–130)
						AUC0-4/D
						V1: 15 (6–43)
						V2: 15 (6–42)
						V3: 16 (6–39)
						r2 AUC0-12: C0, C0.5 = 0.44–0.58 C1, C1.5, C2 = 0.72 to 0.76 C2.5, C4 = 0.84–0.87 C3 = 0.92		r2 AUC0-4: C0, C0.5 = 0.44–0.48 C1, C1.5, C2, C2.5, C3, C4 = 0.83 to 0.88
[112]	22 adults				MEIA- IMx	PK analysis using a one-compartment model with first-order elimination convoluted with a double gamma absorption phase – PK software Ciclo®2.3 3 full PK profiles/patient within 5 days (V1, V2, V3)
						AUC/D: (h.μg/L)/mg tacrolimus	C0/D: (μg/L)/mg tacrolimus	Cmac/D: (μg/L)/mg tacrolimus
	11 CF 30 years (21–43)	3–116 months	D = 0.23 mg/kg/day (0.09–0.47)	AZA (n = 5) or MMF (n =2)		AUC0-12	C0	Cmax	tmax	--
						V1: 182.3±48.2	V1: 9.05±2.29	V1: 31.9±16.9	V1: 1.5±0.6
						V2: 187.4±66.0	V2: 8.91±3.20	V2: 32.4±18.4	V2 : 2.1±1.8
						V3: 169.7±60.5	V3: 8.52±3.10	V3: 26.2±17.7	V3: 1.7±1.2
						AUC0-12/D	C0/D	Cmax/D
						V1: 18.8±9.1	V1 : 0.98±0.61	V1: 3.0±1.3
						V2: 18.5±8.2	V2: 0.89±0.45	V2: 2.9±1.2
						V3: 16.5±6.3	V3: 8.52±3.10	V3: 2.2±0.7
						AUC0-4
						V1: 81.3±39.0
						V2: 80.2±39.3
						V3: 71.0±35.0
						AUC0-4/dose
						V1: 8.1±3.9
						V2: 7.6±3.5
						V3: 6.3±2.7
						Bayesian estimator (AUC0-12): best sampling times: C0, C1.5, C4; r2 = 0.91, mean bias −1.1% (−18.6;16.7%) BE vs Trap on AUC0-12, AUC0-4, Cmax, tmax, C0: bias% < 7.3%; RMSE% < 15%
	11 non-CF 51 years (31–56) p < 0.01	9–86 months	D = 0.1 mg/kg/day (0.06–0.19)	AZA (n = 6)		AUC0-12	C0	Cmax	tmax	--
						V1: 184.0±55.1	V1: 9.62±2.54	V1: 33.1±15.0	V1: 1.4±0.7
						V2: 180.2±59.6	V2: 9.87±2.85	V2: 31.1±17.4	V2: 1.6±1.4
						V3: 183.4±47.0	V3: 9.98±2.49	V3: 30.1±10.8	V3: 1.5±0.8
						AUC0-12/D	C0/D	Cmax/Dose :
						V1: 33.5±14.7	V1: 1.71±0.49	V1: 5.9±3.4
						V2: 33.9±16.7	V2: 1.82±0.72	V2: 6.0±3.8
						V3: 35.8±18.3	V3: 1.90±0.81	V3: 5.7±3.5
						AUC0-4
						V1: 83.7±28.0
						V2: 80.3±33.7
						V3: 80.1±25.9
						AUC0-4/D
						V1: 15.3±7.8
						V2: 15.1±8.5
						V3: 15.9±9.3
						Bayesian estimator (AUC0-12): best sampling times: C0, C1, C3; r2 = 0.96, mean bias −3.6% (−17.4;6.8%) BE vs Trap on AUC0-12, AUC0-4, Cmax, tmax, C0: bias% < 4.6; RMSE% < 15.6

A_IV: intravenous coefficient – ATG: Anti-thymocyte globulin – AZA: Azathioprine – BE: Bayesian estimator – D: Dose – CF: Cystic fibrosis – MMF: Mycophenolate mofetil – NG: Nasogastric – N/R: not reported – Trap: Trapezes.