The Pharmacokinetics of Second-Generation Long-Acting Injectable Antipsychotics: Limitations of Monograph Values

Abstract

Product monographs (also known by terms such as Summary of Product Characteristics and Highlights of Prescribing Information, depending on the jurisdiction) provide essential information to ensure the safe and effective use of a drug. Medical practitioners often rely on these monographs for guidance on matters related to pharmacokinetics as well as indications, contraindications, clinical pharmacology, and adverse reactions. The clinical and scientific information found within these documents, forming the basis for decision making, are presumed to be derived from well-designed studies. The objective of this review is to examine the source and validity of the pharmacokinetic data used in establishing the half-lives and times to steady-state reported in the product monographs of second-generation long-acting injectable antipsychotics. Thus, we have critically evaluated the clinical trials from which the pharmacokinetic parameters listed in the product monographs were determined. In many cases, the pharmacokinetic information presented in product monographs is of limited use to clinicians wishing to optimize the effectiveness and tolerability of second-generation long-acting injectable antipsychotics. Under such circumstances, off-label prescribing practices may actually produce better clinical outcomes than if decisions were made based on the product monographs alone.

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“…The Uchida and Suzuki [164] review included a total of 14 studies with LA injectable FGAs (haloperidol decanoate, n = 11, and fluphenazine decanoate, n = 3), and 4 studies with LA injectable SGAs (LA injectable risperidone, n = 3, and LA injectable olanzapine pamoate, n = 1). Lee et al [153] reached similar conclusions in their 2015 review of the pharmacokinetic data of LA injectable SGAs available in Canada and the USA (LA injectable aripiprazole, olanzapine, risperidone, and 1- and 3-month formulations of paliperidone palmitate).…”

“…While it is generally agreed that for oral SGAs (risperidone, olanzapine, clozapine, quetiapine, and ziprasidone) pharmacokinetic parameters are not sufficient for selection [115], selection of SGAs should be based on efficacy, side effects/tolerability, drug discontinuation-induced withdrawal symptoms and postwithdrawal disorders [1], and drug formulations [4,151]. For LA injectable antipsychotics, pharmacokinetic data in product monographs are of limited value for clinicians to choose the interval of administration [153]. In their recent review, Lee et al [153] recommend using t 1/2 for LA injectable SGAs to decide on the dosing interval in clinical practice.…”

“…For LA injectable antipsychotics, pharmacokinetic data in product monographs are of limited value for clinicians to choose the interval of administration [153]. In their recent review, Lee et al [153] recommend using t 1/2 for LA injectable SGAs to decide on the dosing interval in clinical practice.…”

“…Both the clinical and animal studies reviewed here suggest that an exploration of intermittent dosing strategies in patients is needed. LA injectable antipsychotics can also be given so as to produce intermittent dosing, taking into account the clinical recommendations of Lee et al [153] and Uchida and Suzuki [164]. Intermittent dosing involves that D 2 occupancy levels be high and then low, with each state maintained for approximately equivalent periods of time.…”

“…A recent review of product monographs of all second-generation LA injectable antipsychotics showed that studies to estimate the administration dosing interval do not exist or are not available either for LA injectable risperidone, aripiprazole, or olanzapine, or 1- and 3-month formulations of paliperidone palmitate, and the review concluded that “off-label prescribing practices may actually produce better clinical outcomes than if decisions were based on the product monograph data alone” [153]. The authors noted that t 1/2 (terminal plasma half-life) reported in monographs were based on studies using small sample sizes, a subset of participants with unspecified characteristics, pooling data of all dosage strengths, and times to steady-state determined with visual inspection of concentration-time curves, even worse with the triphasic release of risperidone microspheres “The reported half-life of 3-6 days has no clinical relevance” [153]. A recent example is the 3-month formulation of paliperidone palmitate.…”