Mivacron (Page 3 of 10)

Elimination

The clearance (CL) values of the two more potent isomers, cis-trans and trans-trans , are very high and are dependent on plasma cholinesterase activity (Table 3). The combination of high CL and low distribution volume results in t½ values of approximately 2 minutes for the two more potent isomers. The short t½ and high CL of the more potent isomers are consistent with the short duration of action of MIVACRON.

The CL of the less potent cis-cis isomer is not dependent on plasma cholinesterase. The mean ± S.D. CL was 4.6 ± 1.1 mL/min/kg and t½ was 53 ± 20 minutes in the 18 healthy surgical patients whose data are displayed in Table 3.

Renal and biliary excretion of unchanged mivacurium are minor elimination pathways; urine and bile are important elimination pathways for the two metabolites.

Special Populations

Geriatric Patients (greater than or equal to 60 years)

Two pharmacokinetic/pharmacodynamic studies of MIVACRON have been conducted in geriatric patients. The first study compared the pharmacokinetics and pharmacodynamics of mivacurium in 19 geriatric patients with those in 20 adult patients receiving infusions for as long as 4 to 6 hours. The average infusion rate required to produce 89% to 99% T1 suppression was slightly (~ 14%) lower in geriatric patients. This difference is not regarded as clinically important, but is most likely secondary to differences in pharmacokinetics (i.e., a lower CL of the cis-trans and trans-trans isomers in geriatric patients) (Table 4). The rate of post-infusion spontaneous recovery was not dependent on duration of infusion and appeared to be comparable in these geriatric patients and adult patients. Two pharmacodynamic studies in which patients received infusions for a shorter duration (2 to 3 hours) have shown that the infusion rate requirements were lower (by 38%) in geriatric patients (64 to 86 years of age) than in younger patients (18 to 41 years of age).

Table 4. Stereoisomer Pharmacokinetic Parameters* of Mivacurium in ASA Physical Status I-II Adult Patients [18-58 Years] and Geriatric Patients [60-81 Years] During Opioid/Nitrous Oxide/Oxygen Anesthesia
Parameter Isomer Adult Patients (n = 12) Geriatric Patients (n = 8)
Plasma Clearance (mL/min/kg) trans-trans isomer 54 (34 — 129) 32 (18 — 55)
cis-trans isomer 91 (27 — 825) 47 (24 — 93)
* Values shown are median (range).

The second pharmacokinetic/pharmacodynamic study showed no clinically important differences in the pharmacokinetics of the individual isomers nor the ED95 determined for 36 young adult patients (18 to 40 years) and 35 geriatric patients (greater than or equal to 65 years) during opioid/nitrous oxide/oxygen anesthesia. Following infusions for up to 3.5 hours in these patients, the rate of spontaneous recovery was slightly (~ 2 to 4 minutes, on average) slower in the geriatric patients than in young adult patients.

In a third study of the pharmacodynamics of 0.1 mg/kg MIVACRON administered to eight geriatric patients (68 to 77 years) and nine adult patients (18 to 49 years) during N2 O/O2 /isoflurane anesthesia, the time to onset was approximately 1.5 minutes slower in geriatric patients than in adult patients. In addition, the clinical duration was slightly (~ 3 minutes, on average) longer in geriatric patients than in adult patients; these differences are not considered clinically important.

Although these studies showed conflicting findings, in general, the clearances of the more potent isomers are most likely lower in geriatric patients. This difference does not lead to clinically important differences in the ED95 of MIVACRON or the infusion rate of MIVACRON required to produce 95% T1 suppression in geriatric patients. However, the time to onset may be slower, the duration may be slightly longer, the rate of recovery may be slightly slower, therefore MIVACRON requirements may be lower in geriatric patients.

Patients with Renal Disease

An early clinical trial showed that the clinically effective duration of action of 0.15 mg/kg MIVACRON was about 1.5 times longer in kidney transplant patients than in healthy patients, presumably due to reduced clearance of one or more isomers. A second study was conducted in seven patients with mild to moderate renal impairment, eight patients with severe renal dysfunction (not undergoing transplantation), and 11 patients with normal renal function. This study showed that the pharmacokinetics of the more potent (cis-trans and trans-trans) isomers were not statistically significantly affected by renal impairment or failure (Table 5). However, the CL of the cis-cis isomer was lower and the t½ values of the cis-cis isomer and metabolites were longer in patients with renal impairment or failure than in patients with normal renal function. The second study also showed that there were no differences in the average infusion rate required to produce 89% to 99% T1 suppression, nor were there any differences in the post-infusion recovery profile among these populations (Table 5). A third study in a similar population showed that patients with renal dysfunction had a longer duration and a slower rate of recovery than patients with normal renal function. This study did, however, confirm that there were no differences in the average infusion rate required to produce 89% to 99% T1 suppression in these patient populations. Therefore, although there were minor differences in the pharmacokinetics of the cis-cis isomer and metabolites, there were no clinically significant differences in the infusion rate requirements of MIVACRON in patients with mild, moderate, or severe renal dysfunction receiving infusions of MIVACRON for an average of 1 to 2 hours; however, the duration may be longer and the rate of recovery may be slower following administration of MIVACRON in some patients with renal dysfunction.

Table 5. Stereoisomer Pharmacokinetic Parameters* of Mivacurium in ASA Physical Status I-II Adult Patients with Normal Renal Function [Serum Creatinine less than or equal to 1 mg/dL], Patients with Mild to Moderate Renal Dysfunction [Serum Creatinine 1.3 to 2.7 mg/dL] and Patients with Severe Renal Dysfunction [Serum Creatinine greater than 6.2 mg/dL] During Opioid/Nitrous Oxide/Oxygen Anesthesia
Parameter Isomer Normal Renal Function (n = 10) Mild to Moderate Renal Dysfunction (n = 8) Severe Renal Dysfunction (n = 7)
Plasma Clearance (mL/min/kg) trans-trans isomer 54 (19 — 91) 49 (43 — 59) 53 (17 — 82)
cis-trans isomer 97 (28 — 215) 93 (72 — 115) 110 (23 — 199)
cis-cis isomer 4 (2.9 — 5.4) 2.5 (1.9 — 3.8) 2.8 (2.1 — 4.7)
Volume of Distribution (mL/kg) trans-trans isomer 179 (67 — 492) 243 (119 — 707) 238 (93 — 397)
cis-trans isomer 303§ (97 — 776) 474 (284 — 908) 416|| (64 — 802)
cis-cis isomer 287 (169 — 424) 323 (254 — 473) 276 (213 — 351)
Half-life (min) trans-trans isomer 2.6 (1 — 6.8) 3.6 (1.7 — 10.7) 3.2 (1.6 — 4.1)
cis-trans isomer 2.3§ (0.7 — 5.2) 3.7 (2.2 — 6.9) 2.6|| (1.2 — 5.1)
cis-cis isomer 52 (28 — 80) 90 (66 — 103) 73 (34 — 111)
25% to 75% Recovery Index (min) 10.8 (7.3 — 19.9) 9.2 (5.2 — 13.8) 10.3§ (4.1 — 14.2)
* Values shown are mean (range).† Volume of distribution during the terminal elimination phase.‡ n = 9§ n = 8|| n = 6¶ n = 11

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