Paliperidone, also known as 9-hydroxyrisperidone, is a benzisoxazole antipsychotic that is the major active metabolite of risperidone. Paliperidone is available in an extended release oral tablet as well as a long-acting injectable suspension for intramuscular (IM) use. As per the product monograph, the recommended initiation regimen of paliperidone long-acting injectable is 150 mg on day 1 and 100 mg on day 8 (±4 days), both administered in the deltoid muscle in order “to attain therapeutic concentrations rapidly.” The monograph also recommends that subsequent maintenance doses be given monthly, “administered in either the deltoid or gluteal muscle.” This latter point may be misinterpreted by some clinicians to imply that administering the same maintenance dose of paliperidone long-acting into the deltoid or gluteal muscle is interchangeable and thus therapeutically equivalent. The objective of this report was to review the current pharmacokinetic literature to determine if administering paliperidone long-acting injectable into the deltoid or gluteal muscle is therapeutically equivalent.
FACTORS AFFECTING DRUG ABSORPTION AND BIOAVAILABILITY OF AN IM-ADMINISTERED DRUG
Compared with intravenous administration, IM injections produce lower but more sustained blood concentrations. This is, in part, the result of the injection creating a “depot” in the muscle tissue that acts as a repository for the drug. The rate of absorption from the depot into the vasculature is influenced by many factors including formulation.1,2 In general, aqueous solutions have a faster absorption rate compared with oleaginous solutions. Some other vehicles used to control the rate of absorption of IM injectables include (1) suspensions or colloids in aqueous and oleaginous solvents, (2) oil-in-water emulsions, and (3) water-in-oil emulsions. Different salts of the active compound can also be taken advantage of to reduce the dissolution rate of a drug that in turn reduces the rate of absorption. In the case of paliperidone long-acting injectable, it is formulated as an extremely low water-soluble nanocrystal suspension of the palmitate ester of 9-hydroxyrisperidone. After IM injection, paliperidone palmitate particles slowly dissolve and are then hydrolyzed by serine esterases to active paliperidone before entering into the systemic circulation.
Good IM injection technique not only mitigates pain and injury, it can also impact bioavailability of the administered drug.3 Intramuscular injections are intended to penetrate the striated muscle fibers found under the subcutaneous layer of skin. The primary sites for IM injections include the gluteal, deltoid, and vastus lateralis muscles. Poor injection technique may result in the drug being deposited in the subcutaneous adipose tissue—a region that is much less vascular than muscle tissue. The consequence of this unintentional administration of drug into adipose tissue includes a slower and more erratic rate of absorption that may be incomplete. In general, longer needles are used for IM gluteal injections to ensure that the drug passes all the way through the fat into the muscle.
Absorption and bioavailability of IM injectables from the depot site into the vasculature are also dependent on physiological factors that include obesity, exercise, and local blood flow. With regards to the latter, increased blood flow allows for a greater absorption rate of the drug while sparse perfusion of the tissues (as seen in patients with circulatory failure) can prolong the absorption. Under normal circumstances (resting state), the deltoid site has been shown to have a more prominent muscle blood flow compared with the gluteal and vastus lateralis muscles.4 In contrast to the resting state, certain exercises such as running may induce greater blood flow to the legs, accelerating absorption from both the vastus and gluteal sites. As mentioned previously, both injection technique and vasculature are important determinants of absorption rate. These factors may be compromised when the patient is obese because of the difficulty in reaching the musculature through the thicker layers of adipose tissue. This leads to a greater probability that the drug will be administered to the subcutaneous areas, potentiating the effect of drug leakage from its encapsulation and subsequently reducing bioavailability.
Taken together, all these factors and their interactions can certainly lead to significant variability in the rate and extent of drug absorption. As such, any assertion that an IM injectable administered in either the deltoid or the gluteal muscle is therapeutically equivalent must be substantiated using comprehensive pharmacokinetic studies.
PHARMACOKINETICS OF PALIPERIDONE PALMITATE
A current examination of the literature describing the pharmacokinetics of paliperidone palmitate suggests differences in absorption rate and maximum plasma concentrations (Cmax) at the gluteal and deltoid injection sites. In a 25-week randomized, multicenter, crossover study, stable outpatients (n = 252) were randomly assigned to 1 of 3 paliperidone palmitate dose groups (50, 75, or 100 mg) and within each dose group to 1 of 2 treatment sequences (deltoid muscle followed by gluteal muscle or the reverse).5 In the first phase, participants were administered paliperidone palmitate IM on days 1, 8, 36, and 64 in either the deltoid or gluteal muscle as per randomization. In the second phase, the participants were crossed-over from deltoid to gluteal (or gluteal to deltoid) and were given paliperidone palmitate IM on days 92, 120, and 148. The data showed that treatment initiation of paliperidone palmitate in the deltoid muscle, compared with the gluteal muscle, produced a higher median paliperidone concentration at day 8. Any other conclusions regarding pharmacokinetic differences between deltoid and gluteal administration are not possible because this study was conducted during a time of drug accumulation and not steady state. Had the crossover phase taken place during steady state conditions, changes in plasma concentrations would have provided more conclusive data regarding the bioequivalence of these 2 sites of administration.
In a more recent randomized, single-dose, open-label, dose proportionality study of paliperidone palmitate (n = 201), Cleton et al,6 have shown a manifest disparity between specific exposure parameters at the 2 IM sites. Although this study was designed to evaluate dose proportionality, it also determined certain pharmacokinetic parameters such as the area under the plasma concentration time curve from time zero to last observation and infinity (AUClast and AUC∞, respectively) using the deltoid and gluteal injection sites of 4 fixed paliperidone palmitate doses (ie, 25, 50, 100, 150 mg). The median Cmax (dose normalized to 50 mg) was found to be higher after deltoid injection compared with gluteal injection, and the calculated geometric mean Cmax ratios (%) for deltoid/gluteal were as follows: 25 mg (119.9%), 50 mg (119.9%), 100 mg (108.8%), and 150 mg (164.9%). This wide range of values is the basis for the following statement in the product monograph: “Following intramuscular injection of single doses (25–150 mg) in the deltoid muscle, on average, a 28% higher Cmax was observed compared with injection in the gluteal muscle.”1 This is concerning as the observed Cmax for the 150 mg dose is considerably higher (ie, 65%) than the average value reported in the product monograph. Consistent with a higher Cmax, the time to maximum plasma concentration (tmax) and half-life (t1/2) of paliperidone palmitate 150 mg were reported to be shorter when administered in the deltoid muscle compared with gluteal muscle (tmax, 14 vs 17 days; t1/2, 40.6 vs 49.1 days, respectively). Apart from Cmax, the data showed that the median dose-normalized (to 50 mg) paliperidone plasma concentration 2 to 3 weeks after administration was numerically lower when injected into the gluteal muscle compared with the deltoid muscle. This is consistent with the observation that absorption from the gluteal site into the vasculature is slower. However, it is also possible that some of the drug was administered into the adipose tissue, and it must be kept in mind that steady state has not been achieved during the measurements and this could also be a factor in the observed differences. Because of the small sample size and the high interpatient variability, the study does not reflect a formal bioequivalency comparison; however, the results and discussion do seem to imply that the IM sites are not interchangeable.
A further issue that compounds the complexity of paliperidone palmitate pharmacokinetics is its exhibition of flip-flop kinetics. For example, for an oral agent that follows a simple, linear, 1-compartmental model, the rate of elimination (kel) is marginal to the rate of absorption (ka), allowing the half-life to be determined by the kel. However, in flip-flop kinetics, the scenario is switched (kel > ka) where the elimination half-life is now controlled by the absorption rate. Thus, a faster absorption rate (ie, via deltoid administration) would lead to a shorter elimination half-life. Although, the data published by Cleton et al6 described previously found differences in the parameters of interest between the 2 absorption routes, they did not measure the ka specifically. Nevertheless, in a population pharmacokinetic study of pooled data from 1795 subjects, Samtani et al7 reported that the ka was dependent on many variables including injection site. Using a first-order conditional estimation method and a deconvolution modeling technique, they were able to profile pharmacokinetic parameters for the 2 IM sites in a range of doses (25–150 mg eq). They showed that the ka of paliperidone was influenced by sex, age, injection volume, and injection site. In the latter case, the deltoid muscle produced a shift factor of 1.23. The US Food and Drug Administration (FDA) also reviewed this data and commented that “compared with deltoid injections, repeated administration in the gluteal muscle resulted in a delayed time to achieve steady state (approximately 4 weeks longer).”8
The FDA also evaluated the effects of administering paliperidone palmitate in either the deltoid or the gluteal muscle using data from 3 phase 1 clinical trials with extensive pharmacokinetic sampling and in 1 phase 3 trial with sparse sampling. The review states that the injection of paliperidone palmitate in the deltoid muscle consistently resulted in higher plasma concentrations compared with injections in the gluteal muscle. Furthermore, the observed Cmax and AUC were 20% to 50% higher after injection in the deltoid muscle compared with the gluteal muscle.8
DISCUSSION AND CLINICAL IMPLICATIONS
Concern regarding the therapeutic equivalency of deltoid versus gluteal administration of paliperidone palmitate arises when one considers noteworthy differences observed in pharmacokinetic parameters that include Cmax ratios, tmax, ka, and t1/2 between the 2 primary IM sites.6,7 If injection technique is good, the AUC0-∞ and AUCSS (at steady state) of equivalent doses of paliperidone palmitate administered into the deltoid or gluteal muscle will be the same. Indeed, this has been reported in the single-dose study as well as the population-based pharmacokinetic analysis discussed previously.6,7 Thus, the differences observed in Cmax, tmax, Ka, and t1/2, between the 2 routes of administration will result in the alteration of the biexponential plasma concentrations versus time plots. To this end, higher Cmax, shorter tmax, greater Ka, and shorter t1/2 were noted when paliperidone palmitate was injected into the deltoid compared with the gluteal muscle, which will result in a steeper upward slope that represents the initial absorption phase of the curve as well as a steeper downward slope at the terminal phase of the curve. Despite the different pharmacokinetic curves exhibited when paliperidone palmitate is administered at the different sites, the median steady state plasma concentration of paliperidone is expected to be the same since both volume of distribution and clearance remain unchanged. Nonetheless, it is important to note that the Cmin ratio (gluteal/deltoid) is likely to be similar to the Cmax ratio (deltoid/gluteal). Thus, for a 150-mg dose of paliperidone palmitate administered in the deltoid compared with the gluteal muscle, the Cmin could theoretically be as much as 65% lower.
From a clinical perspective, Cmax coincides with a period where short-term adverse effects are most likely to occur. Similarly, Cmin coincides with a period where the therapeutic effect of a drug is in jeopardy if it falls below the plasma concentration needed for response. Thus, if the Cmax ratio (deltoid/gluteal) of 150 mg paliperidone is 1.65 (65% higher), then the potential for short-term adverse effects within days of the injection is possible. Perhaps more importantly, if the Cmin ratio (gluteal/deltoid) is 65% lower, there is the potential for breakthrough symptoms days before the next scheduled dose. There is also the potential for unforeseen consequences if a patient stabilized using 1 route of injection is switched to the other. For example, consider a patient that has been treated and stabilized on paliperidone palmitate 150 mg administered every 4 weeks into the gluteal muscle for more than a year and then switched to have it administered via the deltoid muscle. Based on the different pharmacokinetic profiles presented previously, there is the possibility that the plasma concentration of paliperidone will fall below an effective therapeutic concentration needed for response before the next scheduled injection. In such cases, physicians may resort to shortening the dosing interval of paliperidone palmitate to every 3 weeks rather than every 4 weeks when administering via the deltoid muscle.
According to both the FDA Guidance for Industry as well as the International Conference of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, bioequivalence is “the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.”9 The “extent” to which a drug becomes available and reaches the systemic circulation is the drug's bioavailability. This is determined by measuring the AUC. As such, we can say that paliperidone palmitate administered either into the deltoid or gluteal muscle is equally bioavailable. On the other hand, the “rate” at which a drug becomes available is determined by its absorption rate. In this case, the data reviewed previously show that the rate of absorption for paliperidone is quicker when administered via the deltoid compared with the gluteal muscle.
Thus, according to the aforementioned definition and findings, administering paliperidone palmitate via the deltoid muscle versus the gluteal muscle is not bioequivalent. Consequently, failure to show bioequivalence implies that administering paliperidone palmitate into the deltoid versus gluteal muscle is also not therapeutically equivalent. By definition, drugs are considered to be therapeutically equivalent if they meet the criteria of both bioequivalence and pharmaceutical equivalence (ie, contain identical amounts of the same active drug ingredient in the same dosage form and route of administration).
To be clear, the product monograph for paliperidone palmitate does not state that the deltoid and gluteal injection sites are interchangeable for maintenance treatment. However, it does state that the maintenance doses can be “administered in either the deltoid or gluteal muscle,” leading some clinicians to believe that these site are interchangeable and thus therapeutically equivalent. We believe that bioequivalence and thus therapeutic equivalence between these sites cannot be established based on the current published pharmacokinetic data. Therefore, clinicians should be cognizant about these differences when giving long-acting antipsychotics via different IM sites. In addition, long-term comprehensive studies are required to fully characterize the pharmacokinetic differences for paliperidone palmitate administered in the deltoid versus the gluteal muscle.
AUTHOR DISCLOSURE INFORMATION
R.M.P. has received consulting fees from Janssen, Lundbeck, Otsuka, Pfizer, and Sunovion, and is on the speaker's bureau for AstraZeneca, Janssen, Lundbeck, Otsuka, and Pfizer. He also received grants from the Canadian Institutes of Health Research.
W.G.H. has received consulting fees from MDH Consulting, In Silico (no honorarium), Novartis, Eli Lilly, Roche, Otsuka, and Lundbeck. He also received grants from the Canadian Institutes of Health Research.
A.M.B. has received grants from Bristol-Myers Squibb and the Canadian Institutes of Health Research.
J.Y. and A.C.C. declare no conflicts of interest.