TABLE 1

Intravenous methadone pharmacokinetic parameters

Subjects received 6.0 mg i.v. methadone HCl at all sessions. Results are the arithmetic mean ± S.D., except area under the plasma concentration-time curve (AUC) ratios (ritonavir-lopinavir/control), which are the geometric mean (90% confidence interval); n = 12, except renal clearances and EDDP formation clearances (n = 10, due to incomplete urine collections in two subjects).

	R-methadone			S-methadone
	Control	Acute Ritonavir-Lopinavir	Steady-State Ritonavir-Lopinavir	Control	Acute Ritonavir-Lopinavir	Steady-State Ritonavir-Lopinavir
C_max (ng/ml)	56 ± 28	36 ± 13^*	36 ± 17^*	78 ± 35	44 ± 17^*	45 ± 22^*
AUC_0–96 (ng ⋅ h ⋅ ml⁻¹)	304 ± 81	213 ± 102^*	234 ± 111^*	441 ± 142	244 ± 161^*	312 ± 201^*
AUC_0–∞ (ng ⋅ h ⋅ ml⁻¹)	427 ± 152	304 ± 160^*	354 ± 213	547 ± 215	313 ± 238^*	410 ± 284^*
AUC_0–∞ ratio (ritonavir-lopinavir/control)		0.65 (0.54, 0.79)	0.74 (0.59, 0.93)		0.47 (0.34, 0.63)	0.64 (0.50, 0.83)
CL_IV (ml ⋅ kg⁻¹ ⋅ min⁻¹)	1.66 ± 0.57	2.80 ± 1.71^*	2.49 ± 1.41^*	1.37 ± 0.65	3.62 ± 3.17^*	2.49 ± 1.99^*
CL_H (ml ⋅ kg⁻¹ ⋅ min⁻¹)	1.54 ± 0.52	2.63 ± 1.61^*	2.33 ± 1.31^*	1.29 ± 0.63	3.47 ± 3.06^*	2.38 ± 1.92^*
Renal clearance (ml ⋅ kg⁻¹ ⋅ min⁻¹)	0.13 ± 0.09	0.16 ± 0.13	0.14 ± 0.13	0.08 ± 0.05	0.13 ± 0.10	0.10 ± 0.08
Elimination t_1/2 (h)	48 ± 10	52 ± 21	54 ± 24	35 ± 10	37 ± 18	41 ± 15
V_ss (l/kg)	6.2 ± 1.6	10.4 ± 4.9^*	9.3 ± 2.8^*	3.6 ± 1.0	8.3 ± 4.7^*	6.8 ± 3.3
E_H	0.10 ± 0.04	0.17 ± 0.11^*	0.15 ± 0.09^*	0.08 ± 0.04	0.22 ± 0.20^*	0.15 ± 0.13^*

	R-EDDP			S-EDDP
	Control	Acute Ritonavir-Lopinavir	Steady-State Ritonavir-Lopinavir	Control	Acute Ritonavir-Lopinavir	Steady-State Ritonavir-Lopinavir
C_max (ng/ml)	0.39 ± 0.08	0.34 ± 0.12	0.43 ± 0.34	0.74 ± 0.22	0.68 ± 0.23	0.74 ± 0.36
AUC_0–96 (ng ⋅ h ⋅ml⁻¹)	20 ± 5	17 ± 5^*	17 ± 5^*	37 ± 10	32 ± 9	32 ± 8
AUC_∞ (ng ⋅ h ⋅ml⁻¹)	28 ± 7	26 ± 11	23 ± 8	45 ± 12	41 ± 12	40 ± 12
Elimination t_1/2 (h)	48 ± 14	59 ± 35	44 ± 13	37 ± 12	40 ± 15	36 ± 10
AUC_0–96 (EDDP/methadone)	0.08 ± 0.03	0.10 ± 0.05	0.08 ± 0.03	0.10 ± 0.04	0.21 ± 0.17^*	0.15 ± 0.10
AUC_∞ (EDDP/methadone)	0.09 ± 0.05	0.11 ± 0.06	0.08 ± 0.03	0.11 ± 0.04	0.22 ± 0.18^*	0.15 ± 0.11
AUC_0–96 (EDDP/methadone) ratio (ritonavir-lopinavir/control)		1.15 (0.98, 1.36)	1.08 (0.99, 1.17)		1.73 (1.35, 2.22)	1.32 (1.13, 1.55)
EDDP formation clearance (ml ⋅ kg⁻¹ ⋅ min⁻¹)	0.15 ± 0.08	0.17 ± 0.09	0.16 ± 0.08	0.21 ± 0.09	0.41 ± 0.26^*	0.27 ± 0.13

CL_H, hepatic clearance; CL_IV, systemic clearance; E_H, hepatic extraction; V_ss, steady-state volume of distribution.
↵* Significantly different from control (P < 0.05).