Transl Clin Pharmacol.  2015 Dec;23(2):66-74. 10.12793/tcp.2015.23.2.66.

Population pharmacokinetic analysis of the multiple peaks phenomenon in sumatriptan

• Lee J
• Lim MS
• Seong SJ
• Park SM
• Gwon MR
• Han S
• Lee SM
• Kim W
• Yoon YR
• Yoo HD

• KMID: 2351811
• DOI: http://doi.org/10.12793/tcp.2015.23.2.66

Abstract

The objective of this study was to develop a population pharmacokinetic (PK) model for sumatriptan, which frequently shows an atypical absorption profile with multiple peaks. Sumatriptan, a selective agonist for the vascular serotonin (5-HT1) receptor that causes vasoconstriction of the cerebral arteries, is used for the acute treatment of migraine attack with or without aura. Despite its relatively high between-subject variability, few reports have addressed PK modeling of sumatriptan. Plasma data obtained after a single 50-mg oral dose of sumatriptan in 26 healthy Korean male subjects were used. Blood samples were collected 0 (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, and 12 h after dosing. Plasma sumatriptan concentrations were analyzed using UPLC/MS/MS. Population PK analysis was performed using plasma concentration data for sumatriptan with NONMEM (ver. 7.2). A total of 364 concentrations of sumatriptan were captured by a one-compartment model with first-order elimination, and a combined transit compartment model and first-order absorption with lag time was successful in describing the PK with multiple peaks in the absorption phase of sumatriptan. The creatinine clearance as a covariate significantly (P < 0.01) influenced the absorption fraction (f ). The final model was validated through a visual predictive check and bootstrapping with no serious model misspecification.

Keyword

Multiple peaks phenomenon; NONMEM; population pharmacokinetics; sumatriptan

MeSH Terms

Absorption
Cerebral Arteries
Creatinine
Epilepsy
Humans
Male
Migraine Disorders
Plasma
Serotonin
Sumatriptan*
Vasoconstriction
Creatinine
Serotonin
Sumatriptan

Figure

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  Figure 1. Individual plasma concentration versus time plots of sumatriptan. The bold red line is the median value.

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  Figure 2. The scheme of the final PK model of sumatriptan. ka1, absorption rate constant from the depot; ka2, absorption rate constant from the final transit compartment to the central compartment; ktr, identical transfer rate constant of the transit compartment model; f, fraction of the dose absorbed through the absorption compartment; n, number of transit compartments placed before the central compartment; an, the drug amount in the nth compartment; CL, clearance.

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  Figure 3. Final model diagnosis plot produced using the final pharmacokinetic model. (A) Observations (DV) vs. population predictions (PRED) (B) DV vs. individual predictions (IPRED) (C) Conditional weighted residuals (CWRES) vs. PRED and (D) CWRES vs. time (TIME).

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  Figure 4. Visual predictive check plot of the final model 0 and 12 h after a single oral administration of 50 mg sumatriptan. A total of 1,000 datasets were simulated using the final PK parameter estimates. Circles represent the observed sumatriptan plasma concentrations: the 90% confidence interval of the simulated concentrations (gray area), and observed concentration (solid line) of the 5th, median, and 95th percentiles.

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  Figure 5. PK curves from representative individuals showing multiple peaks. Circle, observed value; solid red line, individual predicted value.

Reference

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