Need for Bioequivalence Standards that Reflect the Clinical Importance of the Complex Pharmacokinetics of Paliperidone Palmitate Long-Acting Injectable Suspension.

Paliperidone palmitate is a second generation antipsychotic, approved for the treatment of schizophrenia in the form of the long-acting injectable (LAI) products INVEGA SUSTENNA® (once monthly injection) and INVEGA TRINZA® (once every 3 months injection). Paliperidone palmitate dissolves slowly after deep intramuscular injection before being hydrolyzed to paliperidone and absorbed into the systemic circulation. The pharmacokinetic (PK) profile of the INVEGA SUSTENNA® formulation is biphasic, comprised of an initial relatively fast zero-order input, which allows rapid attainment of therapeutic concentrations without oral supplementation; and a subsequent maintained second-stage, first-order input, allowing for once monthly administration. Changes to the manufacturing processes can substantially alter the release characteristics of paliperidone palmitate LAI and consequently its PK profile. As an example, larger or smaller particle sizes of paliperidone palmitate can result in a delayed or accelerated release of paliperidone into the systemic circulation, respectively. Such changes are clinically relevant, as transient excursions above therapeutic plasma concentrations can be associated with an increased risk of adverse effects, including tachycardia, hypotension, QT prolongation, and extrapyramidal symptoms. Conversely, a delay in attaining therapeutic plasma concentrations of paliperidone on initiation of treatment, or a return to low plasma concentrations before the end of a dosing interval during repeated dosing, increases the risk of relapse. Given the integral relationship of the PK profile to the product's clinical effects, it is important to have bioequivalence standards that reflect the complexity of the paliperidone palmitate LAI PK profile if one is to consider therapeutic equivalence based on simple bioequivalence testing. Although both the EMA and U.S. FDA have product-specific guidelines to determine bioequivalence, their requirements differ substantially. In Canada, no LAI product-specific bioequivalence guidance exists for multiphasic medication delivery systems, and the recently revised Comparative Bioavailability Standards: Formulations Used for Systemic Effects guidance applies only to oral and non-injectable formulations. We recommend that new Canadian standards be developed for multiphasic and biphasic intramuscular / subcutaneous (IM/SC) products, including paliperidone palmitate LAI products, because, similar to modified-release oral dosage forms, a different PK profile in modified-release IM/SC products can result in clinically meaningful differences in safety, efficacy, and tolerability. To ensure bioequivalence for both newly initiated and switch patients, this paper proposes bioequivalence standards that could be adopted in Canada that include two studies, a multiple-dose cross-over study, and a single-dose study with partial AUC metrics.

Academic detailing among psychiatrists - feasibility and acceptability.

Purpose Research has shown that academic detailing (AD), which includes repeated in-person educational messages in an interactive format in a physician's office, is among the most effective continuing medical education (CME) forms for improving prescribing practices and reducing drug costs. The purpose of this paper is to investigate AD's feasibility and acceptability as an educational tool among psychiatrists and its ability to facilitate positive changes in antipsychotic prescribing. Design/methodology/approach All psychiatrists practicing in Southwestern Ontario, Canada were invited to participate. Participants (32/299(10.7 percent)) were provided with two educational sessions by a healthcare professional. Participants evaluated their AD visits and completed a pre- and post-AD questionnaire measuring various prescribing practice aspects. Findings A total of 26 out of 32 (81.3 percent) participants completed the post-AD evaluation; most of them (61.5 percent, n=16) felt that AD gave noteworthy information on tools for monitoring side-effects and 50.0 percent ( n=13) endorsed using these in practice. In total, 13 participants (50.0 percent) felt that the AD sessions gave them helpful information on tools for documenting polypharmacy use, which 46.2 percent ( n=12) indicated they would implement in their practice. No significant differences were found between participants' pre- and post-assessment prescribing behaviors. Practical implications There is great need for raising AD program's awareness and improving physician engagement in this process locally, provincially and nationally. Originality/value To the authors' knowledge, this is the first AD program in Canada to target specialists solely. Participant psychiatrists accepted the AD intervention and perceived it as a feasible CME method.