The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine

Abstract

Aims To investigate the pharmacokinetics of morphine, morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) in healthy volunteers after the administration of morphine by subcutaneous bolus injection (s.c.b.) and subcutaneous infusion (s.c.i.) over 4 h, and to compare the results with the intravenous bolus (i.v.) administration of morphine. Methods Six healthy volunteers each received 5 mg morphine sulphate by i.v., s.c.b. and short s.c.i. over 4 h, on three separate occasions, in random order, each separated by at least 1 week. Plasma samples were assayed for morphine, M6G and M3G. Results After i.v. morphine, the concentrations of morphine, M6G and M3G and their pharmacokinetic parameters were similar to those we have observed previously, in other healthy volunteers (when standardized to nmol l x 1 , for a 10 mg dose to a 70 kg subject). After s.c.b. morphine, similar results were obtained except that the median t max values for morphine and M3G were signi®cantly longer than after i.v. morphine (P<0.001 and P<0.05, respectively), with a trend to a longer t max for M6G (P =0.09). The appearance half-lives after s.c.b. morphine for M6G and M3G were also signi®cantly longer than after i.v. morphine (P =0.03 and P<0.05, respectively). Comparison of log-transformed AUC values indicated that i.v. and s.c.b. administration of morphine were bioequivalent with respect to morphine, M6G and M3G. In comparison with i.v. morphine, morphine by s.c.i. was associated with signi®cantly longer median t max values for morphine (P<0.001), M6G (P<0.001) and M3G (P<0.05), and the mean standardized C max values signi®cantly lower than after both i.v. and s.c.b. morphine (morphine P<0.001, M6G P<0.001 and M3G P<0.01 for each comparison). Comparison of log-transformed AUC values after i.v. and s.c.i. morphine indicated that the two routes were not bioequivalent for morphine (logtransformed AUC ratio 0.78, 90% CI 0.66±0.93), M6G (0.72, 90% CI 0.63±0.82), or M3G (0.65, 90% CI 0.54±0.78). A small stability study indicated no evidence of adsorptive losses from morphine infused over 4 h using the infusion devices from the study. Conclusions Although bioequivalence was demonstrated between the s.c.b. and i.v. routes of morphine administration, the bioavailabilities of morphine, M6G and M3G after s.c.i. were signi®cantly lower than after i.v. administration. However, despite this, the study demonstrates that the subcutaneous route is an effective method for the parenteral administration of morphine.

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

“…( Figure 1 d ). The predicted AUC ∞ and CL estimates were 352 ± 133 nM*hr/70 kg and 1,232 ± 260 mL/min/70 kg, respectively (mean ± SD; Table 3, 18, 25). These predicted data were within a twofold window of the reported mean AUC ∞ values of 290 ± 67 nM*hr/70 kg and CL of 1,584 ± 408 mL/min/70 kg, and the ratio of predicted to observed data was 1.2 and 0.78, respectively.…”

“…After these estimated parameters for the hepatic uptake transport component were implemented into the model, the PK simulation of morphine was conducted using the same trial design as used for the parameter estimation process ( Supplementary Table S1 ). The simulation result of the morphine concentration‐time profiles are shown in Figure 1 a 17, 18, 23, 24, 25, 26 together with observed clinical data from six individual adult subjects. The predicted AUC ∞ and CL estimates were 49.4 ± 10 ng/mL*hr and 17.7 ± 3.8 mL/min/kg, respectively (mean ± SD; Table 3, 18, 25).…”

“…The simulation result of the morphine concentration‐time profiles are shown in Figure 1 a 17, 18, 23, 24, 25, 26 together with observed clinical data from six individual adult subjects. The predicted AUC ∞ and CL estimates were 49.4 ± 10 ng/mL*hr and 17.7 ± 3.8 mL/min/kg, respectively (mean ± SD; Table 3, 18, 25). These values were close to the observed AUC ∞ values of 45.9 ± 7.7 ng/mL*hr and CL of 17.9 ± 7.3 mL/min/kg, and the ratio of predicted to observed data was 1.1 and 0.99, respectively.…”

“…Almost all observed data fell within the 5th to 95th percentile range of the simulations. Among the five clinical trial datasets used for the model validation, morphine PK parameter estimates for AUC ∞ and CL were available from the study by Stuart‐Harris et al 25. ( Figure 1 d ).…”

Pharmacological Management of Cancer-Related Pain

“…C max is 1 hour for the oral route, 30 minutes for the subcutaneous route, and 6 minutes for the intravenous route. 127,128 Once C max is reached, another dose should be given if pain is not adequately controlled.…”