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Impact of Release Mechanism on the Pharmacokinetic Performance of PAUC Metrics for Three Methylphenidate Products with Complex Absorption

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ABSTRACT

Purpose

Investigate the performance of partial area under the drug concentration-time curve (PAUC) metrics (0–3 h) and (3–24 h), for Concerta, Ritalin LA and Focalin XR (different Methylphenidate modified-release formulations). The metrics have been chosen as additional BE metrics for Ritalin LA by the FDA to establish BE for these products due to the early and late peak concentrations critical for treatment of morning and afternoon symptoms of attention deficit hyperactivity disorder (ADHD).

Methods

Two-stage analysis was performed on plasma data for the methylphenidate modified-release products. Simulations using the fitted parameters determined how changes in fast absorption rate constant k0fast, and slow absorption rate constant KAslow affected curve shape and BE determination using Cmax, AUCINF and PAUC.

Results

Sensitivity of the mean PAUC(test)/PAUC(reference) ratios to changes in k0fast and Kaslow were product dependent. Focalin XR mean PAUC(test)/PAUC(reference) ratios for PAUC0–3 h and PAUC3–24 h were most responsive to changes in k0Fast and Kaslow than Concerta and Ritalin LA. The PAUC(test)/PAUC(reference) ratios for (0–3 h) were not responsive to changes to Kaslow. Concerta PAUC (3–24 h) ratios were responsive to changes in Kaslow at ratios less than 1.

Conclusions

Response to PAUC(0–3 h) in the formulations was greater for k0fast than was PAUC(3–24) to changes in KAslow.

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Abbreviations

1-F1:

relative bioavailability fraction of the administered, dose for the extended release compartment 2

ADHD:

attention deficit hyperactive disorder

AUCext :

extrapolated area

AUCinf :

area-under-the-curve to time infinity

AUCT :

area-under-the-curve to time T

AUCT-t :

area-under-the-curve from time T to time t with T defined as 3 h and t being 24 h

BE:

bioequivalence

CI:

confidence intervals

CL:

clearance

D1:

is duration of zero order absorption from the fast release compartment 1

F1:

relative bioavailability fraction of the administered dose for the fast release compartment 1

F2:

process which was lagged to accommodate the duration of absorption for the fast release relative bioavailability fraction of the administered dose, describes the absorption of drug from the extended release compartment 2

FDA:

Food and Drug Administration

IR:

immediate-release

k03:

elimination rate constant

k13:

k0fast-a zero-order absorption rate constant

k23:

KAslow -first-order absorption process

LAG:

time for absorption delay for extended release

PAUC:

partial area under the curve

REFERENCES

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ACKNOWLEDGMENTS AND DISCLOSURES

The views expressed in this manuscript are those of the author and do not reflect the official policy of the FDA. No official support or endorsement by the FDA is intended or should be inferred.

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Authors and Affiliations

  1. Food and Drug, Silver Spring, Maryland, USA

    Andre Jackson

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  1. Andre Jackson
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Correspondence to Andre Jackson.

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Jackson, A. Impact of Release Mechanism on the Pharmacokinetic Performance of PAUC Metrics for Three Methylphenidate Products with Complex Absorption. Pharm Res 31, 173–181 (2014). https://doi.org/10.1007/s11095-013-1150-0

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  • DOI: https://doi.org/10.1007/s11095-013-1150-0

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