Dosing of INVEGA SUSTENNA - Rationale - Maintenance Dose

Doses of paliperidone palmitate extended-release injectable suspension may be expressed in milligram equivalents of paliperidone (active moiety) or milligrams of paliperidone palmitate. Dosage information in this response has been converted to milligrams of paliperidone palmitate to reflect the commercially available dosage strengths in the United States. The conversion factor from mg eq to mg is 1.56.

• INVEGA SUSTENNA doses expressed as 39, 78, 117, 156, and 234 mg of paliperidone palmitate are equal to 25, 50, 75, 100, and 150 mg eq of paliperidone, respectively.

POPULATION PHARMACOKINETIC MODELING

Samtani et al (2009) 4 evaluated the optimal Maintenance Dosing strategy for paliperidone palmitate using a population PK simulation model and data from schizophrenia clinical trials. The authors also investigated the optimal monthly maintenance dose strength of INVEGA SUSTENNA equivalent to paliperidone ER 6 mg.

Population Pharmacokinetic Model Background

A comprehensive population PK model was developed for INVEGA SUSTENNA based on clinical trials of patients with schizophrenia. Pooled data from 1,795 patients and 18,530 PK samples with valid concentration-time points were used to develop the model. The simulation was developed using a 1-compartment disposition model with a zero/first order absorption profile which best described the PK of INVEGA SUSTENNA. The absorption component of the model allowed a fraction of the dose to enter the central compartment relatively quickly via a zero-order process. After a certain lag time, the remaining fraction enters the systemic circulation via a first-order process that determines the shape of the plasma concentration-time curve following injection. PK profiles for 5000 patients were simulated after INVEGA SUSTENNA injections on days 1, 8, 36, and every 4 weeks thereafter. Paliperidone plasma concentrations over 53 weeks were simulated based on final estimates of the population PK model. To evaluate the outcome of simulations, the population median and 90% prediction intervals of simulated plasma concentration vs time profiles after multiple doses were displayed graphically.

The paliperidone ER tablet population PK model was developed using pooled data from 1,368 patients and 21,183 PK samples with valid concentration-time points from all phases of the paliperidone ER clinical trial program. The PK of paliperidone ER was best described as a 2-compartment disposition model with linear elimination from the central compartment. Absorption was modeled with a consecutive zero-order input into a depot compartment and first-order absorption, including lag time, from the depot to the central compartment.

Maintenance Dosing

Population PK simulations for monthly injections of 39, 78, and 156 mg paliperidone palmitate, administered either in the deltoid or gluteal muscle, illustrated that paliperidone plasma concentrations on day 36 onwards were similar regardless of the muscle site used for the maintenance injection. This suggests that gluteal or deltoid injections of paliperidone palmitate can be used interchangeably during maintenance treatment (Figure: Similar Population PK Simulations for Deltoid and Gluteal Muscle Injections During Paliperidone Palmitate Maintenance Therapy).

Similar Population PK Simulations for Deltoid and Gluteal Muscle Injections During Paliperidone Palmitate Maintenance Therapy 4

Population PK Projection for the Suggested Paliperidone Palmitate Initiation (234 mg on Day 1 and 156 mg on Day 8) and Maintenance (117 mg Once Monthly) Dosing Regimen. Similarity between exposure profiles for 117 mg and 234 mg paliperidone palmitate has been shown for up to 1 year when compared to 6 and 12 mg paliperidone ER, respectively, using population PK simulated exposures.

Population PK Projection for the Suggested Paliperidone Palmitate Initiation (234 mg on Day 1 and 156 mg on Day 8) and Maintenance (117 mg Once Monthly) Dosing Regimen 4

The authors concluded that based on population PK simulation data, the suggested monthly maintenance dose for INVEGA SUSTENNA should be 117 mg, with a range of 39-234 mg, administered by either deltoid or gluteal muscle injection.

OTHER RELEVANT LITERATURE

Yin et al (2015) 8 proposed that the deltoid and gluteal intramuscular administration sites are not interchangeable for maintenance dosing with INVEGA SUSTENNA. The authors relied on conclusions from a single-dose pharmacokinetic study 9 with INVEGA SUSTENNA (with a limited sample size) and extrapolated to multiple dose and maintenance treatment with INVEGA SUSTENNA.

• Janssen developed a robust population pharmacokinetic model using both single and multiple-dose pharmacokinetic data. 10 The PK model utilized data from 1,795 subjects from six phase 1 trials and five phase 2 and 3 trials with a total of 18,530 PK samples from many different countries and ethnicities.
• The interchangeability between deltoid and gluteal intramuscular injections for maintenance dosing was supported by the submission of the relevant pharmacokinetic and clinical data for once-monthly paliperidone palmitate.
• In addition, in a 25-week randomized, crossover study by Hough et al 11 , there was little difference in plasma paliperidone concentrations between the deltoid and gluteal sites for a given dose when at apparent steady state.
• It is true that there may be difficulty in reaching the musculature in the gluteal injection site due to the thickness of the adipose tissue (likely from BMI>30), and this is a primary reason that the two initiation doses of INVEGA SUSTENNA are required to be administered in the deltoid muscle in addition to the requirement for weight-based selection of the appropriate needle size for administration.

LITERATURE SEARCH

A literature search of MEDLINE ® , Embase ® , BIOSIS Previews ® , and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 26 March 2024.

References

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