Biodistribution of Lipid 5, mRNA, and Its Translated Protein Following Intravenous Administration of mRNA-Encapsulated Lipid Nanoparticles in Rats.

RNA-based therapeutics and vaccines represent a novel and expanding class of medicines, the success of which depends on the encapsulation and protection of mRNA molecules in lipid nanoparticle (LNP)-based carriers. With the development of mRNA-LNP modalities, which can incorporate xenobiotic constituents, extensive biodistribution analyses are necessary to better understand the factors that influence their in vivo exposure profiles. This study investigated the biodistribution of heptadecan-9-yl 8-((2-hydroxyethyl)(8-(nonyloxy)-8-oxooctyl)amino)octanoate (Lipid 5)-a xenobiotic amino lipid-and its metabolites in male and female pigmented (Long-Evans) and nonpigmented (Sprague Dawley) rats by using quantitative whole-body autoradiography (QWBA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques. After intravenous injection of Lipid 5-containing LNPs, 14C-containing Lipid 5 ([14C]Lipid 5) and radiolabeled metabolites ([14C]metabolites) were rapidly distributed, with peak concentrations reached within 1 hour in most tissues. After 10 hours, [14C]Lipid 5 and [14C]metabolites concentrated primarily in the urinary and digestive tracts. By 24 hours, [14C]Lipid 5 and [14C]metabolites were localized almost exclusively in the liver and intestines, with few or no concentrations detected in non-excretory systems, which is suggestive of hepatobiliary and renal clearance. [14C]Lipid 5 and [14C]metabolites were completely cleared within 168 hours (7 days). Biodistribution profiles were similar between QWBA and LC-MS/MS techniques, pigmented and nonpigmented rats, and male and female rats, excluding the reproductive organs. In conclusion, the rapid clearance through known excretory systems, with no evidence of redistribution for Lipid 5 or accumulation of [14C]metabolites, provides confidence for the safe and effective use of Lipid 5-containing LNPs. SIGNIFICANCE STATEMENT: This study demonstrates the rapid, systemic distribution of intact and radiolabeled metabolites of Lipid 5, a xenobiotic amino lipid component of novel mRNA-LNP medicines, and its effective clearance without substantial redistribution after intravenous administration; additionally, findings were consistent between different mRNAs encapsulated within LNPs of similar composition. This study confirms the applicability of current analytical methods for lipid biodistribution analyses, and taken together with appropriate safety studies, supports the continued use of Lipid 5 in mRNA-medicines.

A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against Chikungunya virus.

Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 ( NCT03829384 ). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18-50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6 mg kg-1, or two weekly doses at 0.3 mg kg-1. At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 µg ml-1) across doses that persisted for ≥16 weeks at 0.3 and 0.6 mg kg-1 (mean t1/2 approximately 69 d). A second 0.3 mg kg-1 dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted.

Napabucasin Drug-Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers.

Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.

mRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease.

Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α). G6Pase-α is critical for maintaining interprandial euglycemia. GSD1a patients exhibit life-threatening hypoglycemia and long-term liver complications including hepatocellular adenomas (HCAs) and carcinomas (HCCs). There is no treatment for GSD1a and the current standard-of-care for managing hypoglycemia (Glycosade®/modified cornstarch) fails to prevent HCA/HCC risk. Therapeutic modalities such as enzyme replacement therapy and gene therapy are not ideal options for patients due to challenges in drug-delivery, efficacy, and safety. To develop a new treatment for GSD1a capable of addressing both the life-threatening hypoglycemia and HCA/HCC risk, we encapsulated engineered mRNAs encoding human G6Pase-α in lipid nanoparticles. We demonstrate the efficacy and safety of our approach in a preclinical murine model that phenotypically resembles the human condition, thus presenting a potential therapy that could have a significant therapeutic impact on the treatment of GSD1a.

Mass balance and pharmacokinetics of an oral dose of 14 C-napabucasin in healthy adult male subjects.

This phase 1, open-label study assessed14 C-napabucasin absorption, metabolism, and excretion, napabucasin pharmacokinetics, and napabucasin metabolites (primary objectives); safety/tolerability were also evaluated. Eight healthy males (18-45 years) received a single oral 240-mg napabucasin dose containing ~100 µCi14 C-napabucasin. Napabucasin was absorbed and metabolized to dihydro-napabucasin (M1; an active metabolite [12.57-fold less activity than napabucasin]), the sole major circulating metabolite (median time to peak concentration: 2.75 and 2.25 h, respectively). M1 plasma concentration versus time profiles generally mirrored napabucasin; similar arithmetic mean half-lives (7.14 and 7.92 h, respectively) suggest M1 formation was rate limiting. Napabucasin systemic exposure (per Cmax and AUC) was higher than M1. The total radioactivity (TRA) whole blood:plasma ratio (AUClast : 0.376; Cmax : 0.525) indicated circulating drug-related compounds were essentially confined to plasma. Mean TRA recovery was 81.1% (feces, 57.2%; urine, 23.8%; expired air, negligible). Unlabeled napabucasin and M1 recovered in urine accounted for 13.9% and 11.0% of the dose (sum similar to urine TRA recovered); apparent renal clearance was 8.24 and 7.98 L/h. No uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites, suggesting napabucasin was mainly cleared by reductive metabolism. All subjects experienced mild treatment-emergent adverse events (TEAEs), the majority related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Napabucasin was absorbed, metabolized to M1 as the sole major circulating metabolite, and primarily excreted via feces. A single oral 240-mg dose was generally well tolerated.

Pharmacokinetics, Safety, and Tolerability of a 2-Month Dose Interval Regimen of the Long-Acting Injectable Antipsychotic Aripiprazole Lauroxil: Results From a 44-Week Phase I Study.

BACKGROUND: Aripiprazole lauroxil (AL) is a long-acting injectable antipsychotic approved for treatment of schizophrenia in adults. Approved AL doses and dosing regimens include 441 mg monthly, 662 mg monthly, and 882 mg monthly or every 6 weeks (q6wk), as well as the most recently approved dose, 1064 mg, administered every 2 months. OBJECTIVE: Pharmacokinetics, safety, and tolerability of an AL regimen with a dose interval of every 2 months (1064 mg) were compared with two other regimens available as monthly and q6wk options. METHODS: This study evaluated pharmacokinetics of AL given at a higher dosage strength (1064 mg) and at a longer dose interval (every 8 weeks [q8wk]) than previously studied. Patients with schizophrenia or schizoaffective disorder entering this 44-week, phase I, open-label, multicenter study had no recent exposure to aripiprazole and were maintained on other oral antipsychotics throughout the study. Patients were randomized to one of three AL dose regimens for 24 weeks (four 1064-mg injections [q8wk], five 882-mg injections [q6wk], or seven 441-mg injections [q4wk], with the last AL exposure at week 24). Oral aripiprazole was prohibited. Patients were followed for an additional 20 weeks to assess terminal aripiprazole plasma concentrations and ongoing safety. Plasma concentration samples were obtained at regular intervals to provide pharmacokinetic data for the duration of AL exposure and to measure persistence of plasma aripiprazole concentrations after AL discontinuation. RESULTS: Eligible patients received AL 1064 mg q8wk (n = 35), 882 mg q6wk (n = 34), or 441 mg q4wk (n = 35). Overall, 103/104 (99.0%) patients were taking concomitant non-aripiprazole oral antipsychotic medications during the study. All three AL dose regimens provided continuous exposure to aripiprazole. Mean aripiprazole concentrations from the 1064-mg q8wk regimen were comparable to the 882-mg q6wk regimen and higher than the 441-mg q4wk regimen. Overall incidence by group of any adverse events (AEs) throughout the study was 68.6% (1064 mg q8wk), 50.0% (882 mg q6wk), and 65.7% (441 mg q4wk). The most common AE across regimens was injection-site pain (range 8.6%-11.4%). Serious AEs were reported by eight patients (all but one [increased psychosis in one patient, 441-mg q4wk group] considered unrelated to study drug). Discontinuations due to AEs were reported for 2.9%, 11.8%, and 5.7% of patients receiving the 8-, 6-, and 4-week regimens, respectively. AEs of akathisia, dyskinesia, and dystonia occurred in 2.9%, 8.6%, and 5.7% of patients in the 1064-mg q8wk group, 8.8%, 0%, and 2.9% in the 882-mg q6wk group, and 8.6%, 0%, and 0% in the 441-mg q4wk group, respectively. CONCLUSIONS: AL 1064 mg q8wk provided continuous exposure to aripiprazole throughout the 8-week dosing interval and had a safety profile consistent with the 4- and 6-week regimens. These findings were used to support FDA approval of the 1064-mg dose administered every 2 months. REGISTRATION: Clinicaltrials.gov: NCT02320032.

Disease pharmacokinetic-pharmacodynamic modelling in acute intermittent porphyria to support the development of mRNA-based therapies.

BACKGROUND AND PURPOSE: Acute intermittent porphyria (AIP) results from haplo-insufficiency of the porphobilinogen deaminase (PBGD) gene encoding the third enzyme in the haem biosynthesis pathway. As liver is the main organ of pathology for AIP, emerging therapies that restore enzyme hepatic levels are appealing. The objective of this work was to develop a mechanistic-based computational framework to describe the effects of novel PBGD mRNA therapy on the accumulation of neurotoxic haem precursors in small and large animal models. EXPERIMENTAL APPROACH: Liver PBGD activity data and/or 24-hr urinary haem precursors were obtained from genetic AIP mice and wild-type mice, rats, rabbits, and macaques. To mimic acute attacks, porphyrogenic drugs were administered over one or multiple challenges, and animals were used as controls or treated with different PBGD mRNA products. Available experimental data were sequentially used to build and validate a semi-mechanistic mathematical model using non-linear mixed-effects approach. KEY RESULTS: The developed framework accounts for the different biological processes involved (i.e., mRNA sequence, release from lipid nanoparticle and degradation, mRNA translation, increased PBGD activity in liver, and haem precursor metabolism) in a simplified mechanistic fashion. The model, validated using external data, shows robustness in the extrapolation of PBGD activity data in rat, rabbit, and non-human primate species. CONCLUSION AND IMPLICATIONS: This quantitative framework provides a valuable tool to compare PBGD mRNA drug products during early preclinical stages, optimize the amount of experimental data required, and project results to humans, thus supporting drug development and clinical dose and dosing regimen selection.

Characterization of the Pharmacokinetics of Samidorphan in Healthy Volunteers: Absolute Bioavailability and the Effect of Food and Age.

BACKGROUND AND OBJECTIVES: Samidorphan (SAM) is a novel µ-opioid receptor antagonist. We report clinical pharmacokinetic (PK) properties of SAM following different routes of administration, and the effects of food and age on the PK of SAM following oral administration in healthy volunteers. METHODS: An open-label, fixed-sequence study (study 1, N = 10) examined the PK parameters following intravenous, sublingual, and oral exposure to SAM to determine absolute bioavailability. A double-blind, placebo-controlled study (study 2, N = 45) compared the PK in participants aged 18-40 years (cohort 1, n = 30) and ≥ 65 years (cohort 2, n = 15) who received a single oral dose of SAM 10 mg under fed (cohort 1 only) or fasted conditions. RESULTS: In study 1, intravenous SAM had a plasma clearance of 33.7 L/h, volume of distribution of 341 L, and elimination half-life of 7-8 h. SAM was well-absorbed following sublingual or oral administration and reached peak concentrations (Cmax) within 2 h, with absolute bioavailability of 71% (sublingual) and 69% (oral). In study 2, concentration-time profiles were similar under fed and fasted conditions (cohort 1) and for young and elderly participants from both cohorts; 90% confidence intervals for the geometric least squares mean ratios for Cmax and area under the concentration-time curve from time zero extrapolated to infinity indicated equivalence. CONCLUSIONS: SAM has high bioavailability that is comparable following sublingual and oral administration and is not subject to extensive first-pass metabolism. The PK of orally administered SAM are not affected by food or age.

Pharmacokinetics and safety of deltoid or gluteal injection of aripiprazole lauroxil NanoCrystal® Dispersion used for initiation of the long-acting antipsychotic aripiprazole lauroxil.

BACKGROUND: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia in adults, can be started with either 21 days of daily oral aripiprazole supplementation or a 1-day initiation regimen consisting of a single injection of a NanoCrystal® Dispersion formulation of AL (ALNCD) and a single dose of 30 mg oral aripiprazole. This phase I study assessed the pharmacokinetics and safety of deltoid versus gluteal ALNCD injections. METHODS: Patients with schizophrenia or schizoaffective disorder (N = 47) were randomized 1:1 to receive a single intramuscular dose of ALNCD in the deltoid or gluteal muscle. Plasma samples were collected over 85 days to measure ALNCD concentration by injection site. Relative aripiprazole bioavailability for deltoid versus gluteal injection was assessed based on area under the curve (AUC∞ and AUClast) and maximum concentration (Cmax) values. Adverse events were monitored throughout the study. RESULTS: Plasma aripiprazole concentrations after a single ALNCD injection were comparable between deltoid and gluteal administration. Mean maximum plasma aripiprazole concentrations were 196.1 ng/ml (deltoid) and 175.0 ng/ml (gluteal). Exposure to aripiprazole was similar, with mean AUC∞ values of 6591 day × ng/ml for deltoid and 6437 day × ng/ml for gluteal. Aripiprazole bioavailability was not significantly different between injection sites. ALNCD administration in the deltoid or gluteal muscle was well tolerated, with similar safety profiles at both sites. CONCLUSION: ALNCD demonstrated similar exposure and safety profiles between the two administration sites, suggesting that ALNCD can be given in either the gluteal or the deltoid muscles as a component of the 1-day initiation regimen for AL.

Pharmacokinetic Evaluation of a 1-Day Treatment Initiation Option for Starting Long-Acting Aripiprazole Lauroxil for Schizophrenia.

BACKGROUND: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation. We report findings from a phase 1 study investigating a nanocrystalline milled dispersion of AL (ALNCD) as a potential 1-day initiation regimen. The 1-day initiation regimen is designed to enable rapid achievement of plasma aripiprazole concentrations that are comparable with the 21-day oral initiation regimen. Here, a 6-month pharmacokinetic study compared 2 different initiation regimens for starting AL. METHODS: Patients were randomized 1:1:1:1 to receive 1 of 4 treatments consisting of the 1-day (single ALNCD injection + one 30-mg dose of oral aripiprazole on day 1 only) or the 21-day (15-mg daily dose of oral aripiprazole for 21 days) initiation regimen, each combined with a starting AL dose of either 441 mg or 882 mg. RESULTS: In total, 133/161 patients completed the study. The pharmacokinetic profile of the 1-day initiation regimen was comparable to the 21-day initiation regimen; both achieved aripiprazole concentrations in the therapeutic range within 4 days and remained in a comparable concentration range during treatment initiation. Common adverse events (≥5.0%) were injection-site pain, headache, increased weight, insomnia, dyspepsia, and anxiety. Nine akathisia events occurred (4 events in 4 patients and 5 events in 2 patients in the 1-day and 21-day initiation regimen groups, respectively). CONCLUSIONS: The 1-day initiation regimen resulted in plasma aripiprazole concentrations consistent with the 21-day initiation regimen. Therefore, a single dose of ALNCD with a single 30-mg oral dose of aripiprazole provides an alternative initiation regimen for starting AL.

Population Pharmacokinetic Analysis and Model-Based Simulations of Aripiprazole for a 1-Day Initiation Regimen for the Long-Acting Antipsychotic Aripiprazole Lauroxil.

BACKGROUND AND OBJECTIVES: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation (21-day initiation regimen). An alternative 1-day initiation regimen utilizing a nano-crystalline milled dispersion of AL (ALNCD) plus a single 30 mg oral aripiprazole dose achieved aripiprazole concentrations associated with therapeutic doses of aripiprazole in the same time frame as the 21-day initiation regimen when starting AL (441 or 882 mg). A population pharmacokinetic (PopPK) model was developed to describe aripiprazole pharmacokinetics following administration of ALNCD, AL and oral aripiprazole, and evaluate dosing scenarios likely to be encountered in clinical practice. METHODS: In total, 12,768 plasma aripiprazole concentrations from 343 patients (from 4 clinical studies) were included in the PopPK analysis and used to construct the model. RESULTS: Concomitant administration of the 1-day initiation regimen with all approved AL dosing regimens (441, 662, or 882 mg monthly, 882 mg every 6 weeks, or 1064 mg every 2 months) is predicted to achieve aripiprazole concentrations associated with therapeutic doses of AL using the 21-day initiation regimen within 4 days, maintaining these concentrations until the next AL dose. Administration of the first AL injection 10 days after the 1-day initiation regimen resulted in median aripiprazole concentrations just before the second dose of AL ≥ 77% of that when coadministered on the same day. Coadministration of AL with a single ALNCD injection was predicted to be effective in rapidly re-establishing concentrations associated with therapeutic doses of AL following dose delay. CONCLUSIONS: Model-based simulations demonstrate that the 1-day initiation regimen is suitable for starting treatment with all AL doses, allowing a window of ≤ 10 days between initiation and AL administration. ALNCD may also be used to re-establish concentrations associated with therapeutic doses of AL in conjunction with a delayed AL dose.

A Phase-1 Study Comparing Pharmacokinetic and Safety Profiles of Three Different Dose Intervals of Aripiprazole Lauroxil.

BACKGROUND: Aripiprazole lauroxil (AL) is an FDA-approved treatment for schizophrenia. AL is a non-ester prodrug of aripiprazole that results in extended systemic release of aripiprazole after intramuscular (IM) administration. This Phase-1 study evaluated the pharmacokinetics (PK) and safety of a new AL dose (1064 mg)* for 2-month dose intervals. The study also evaluated 4- and 6-week dose intervals of AL at the 441 mg and 882 mg doses, respectively. METHODS: A total of 139 patients diagnosed with schizophrenia and stabilized on a first-line antipsychotic (other than aripiprazole) were randomized to one of 3 dose/dose-interval groups: a 4-week interval of AL 441 mg (n = 35), a 6-week interval of AL 882 mg (n = 34), and an 8-week interval of AL 1064 mg IM injection (n = 70). After randomization, AL assignment was open label and administered as gluteal injections over 24 weeks. The total number of injections over this time period was related to the interval: 7 injections for the 441 mg group, 5 for the 882 mg group, and 4 for the 1064 mg group. PK and safety assessments occurred every 2 weeks and extended for an additional 20 weeks after the last injection. Patients continued their prior antipsychotic throughout, such that the safety (but not the PK) findings also reflect a second antipsychotic co-prescribed with AL. RESULTS: PK findings: administration of AL 1064 mg every 8 weeks and AL 882 mg every 6 weeks provided continuous exposure to aripiprazole. Compared with the AL 441 mg every 4 weeks group, the longer dose-interval groups had consistently higher plasma concentrations for the entirety of the 6- and 8-week dose intervals for the 882 mg and 1064 mg dose groups. Safety findings: the overall safety profile of the group randomized to the 8 week/1064 mg combination was comparable to the 6 week/882 mg and 4 week/441 mg groups. The most common adverse event (AE) for all groups was injection-site reaction (pain). There was no apparent dose-AE signal for extrapyramidal symptoms, akathisia, sedation, or weight gain. In particular, there was no other safety signal identified with the longest interval/highest-dose AL group of 8 weeks/1064 mg. CONCLUSION: AL allows for a range of dose/dose-interval combinations. The PK results from this study show that a dosing interval of every 8 weeks for the 1064 mg dose resulted in aripiprazole concentrations within the established therapeutic window for AL. There was no safety signal directing any particular concern to any of the three doses/dose intervals studied. All patients continued their primary antipsychotics without any apparent tolerability issue arising from the addition of the AL injections. The results of this study show that 1064 mg AL may be suitable for a 2-month dose interval. The three doses/dose intervals studied have the potential to help clinicians and patients expand their choice of AL treatment to best meet the needs of the individual patient.

Pharmacokinetic Profile of a 2-Month Dose Regimen of Aripiprazole Lauroxil: A Phase I Study and a Population Pharmacokinetic Model.

BACKGROUND: Aripiprazole lauroxil (AL) is a long-acting injectable medication approved for the treatment of schizophrenia. Current AL regimens are 441 mg, 662 mg, and 882 mg administered monthly (every 4 weeks [q4wk]), or 882 mg administered every 6 weeks (q6wk). OBJECTIVE: We examined the feasibility of a 2-month (every 8 weeks [q8wk]) dosing interval of AL in a phase I open-label pharmacokinetic study investigating AL 1064 mg administered q8wk for 24 weeks, followed by 20 weeks of safety and pharmacokinetic measurements (ClinicalTrials.gov ID: NCT02320032). Second, a population pharmacokinetic model (referred to as the 2MPopPK model) was generated using data collected from the present trial, as well as data obtained from earlier studies. METHODS: The phase I study included patients with schizophrenia or schizoaffective disorder maintained on an oral antipsychotic (n = 140) who were assigned to one of three groups: AL 441 mg q4wk, AL 882 mg q6wk, or AL 1064 mg q8wk, with a total of seven, five, or four injections administered, respectively. No oral aripiprazole lead-in supplementation was administered and patients continued on maintenance oral antipsychotics. Pharmacokinetic samples were collected at various time points during the 24-week study period and the 20-week follow-up period. Plasma concentrations obtained from the phase I study were analyzed using non-compartmental methods. Additionally, the data were combined with data collected from prior studies to develop the 2MPopPK model. RESULTS: Following the final injection of AL in the phase I study, maximum aripiprazole concentrations were achieved 24.4-35.2 days after the last dose and persisted for the duration of the study. The mean C avg,ss values were 125.8 ng/ml, 131.1 ng/ml, and 140.7 ng/ml for the 441 mg q4wk, 882 mg q6wk, and 1064 mg q8wk doses, respectively. The mean elimination half-life of aripiprazole following the last dose was 53.9 days for the 1064 mg dose, 55.1 days for the 882 mg dose, and 57.2 days for the 441 mg dose. The 2MPopPK dataset included 14,524 aripiprazole concentrations from 700 patients with schizophrenia. The duration of absorption of aripiprazole was estimated as 43 days (95% confidence interval [CI] 42-45 days), which was preceded by a 3.2-day lag time (95% CI 3.0-3.5 days) for a total duration of input into the systemic circulation of 46 days following intramuscular administration of AL. Multiple-dose simulations showed that the 1064 mg q8wk regimen provides aripiprazole concentrations within the concentration range associated with 441 mg and 882 mg q4wk doses previously demonstrated to be efficacious in a phase III study. CONCLUSION: These data from the phase I study and the 2MPopPK model support the suitability of using the AL 1064 mg dose as a 2-month (q8wk) dose interval option for the treatment of schizophrenia.

Aripiprazole Lauroxil: Pharmacokinetic Profile of This Long-Acting Injectable Antipsychotic in Persons With Schizophrenia.

BACKGROUND: Aripiprazole lauroxil is an extended-release prodrug of aripiprazole for intramuscular injection, approved for schizophrenia treatment. We developed a population pharmacokinetic (PopPK) model to characterize aripiprazole lauroxil PK and evaluate dosing scenarios likely to be encountered in clinical practice. METHODS: Data from 616 patients with schizophrenia, collected from 5 clinical studies, were used to construct the PopPK model. The model was subsequently used to evaluate various dose levels and frequency and the impact of dosing delay on aripiprazole concentrations. FINDINGS: The results of the model indicate that aripiprazole is released into the systemic circulation after 5 to 6 days, and release continues for an additional 36 days. The slow increase in aripiprazole concentration after injection necessitates the coadministration of oral aripiprazole for 21 days with the first injection. Based on the PopPK model simulations, a dosing interval of 882 mg every 6 weeks results in aripiprazole concentrations that fall within the concentration range associated with the efficacious aripiprazole lauroxil dose range (441-882 mg dosed monthly). A 662-mg monthly dose also resulted in aripiprazole concentrations within the efficacious dose range. Aripiprazole lauroxil administration results in prolonged exposure, such that dose delays of 2 to 4 weeks, depending on the dose regimen, do not require oral aripiprazole supplementation upon resumption of dosing. CONCLUSIONS: This PopPK model and model-based simulations were effective means for evaluating aripiprazole lauroxil dosing regimens and management of missed doses. Such analyses play an important role in determining the use of this long-acting antipsychotic in clinical practice.

Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia.

Aripiprazole lauroxil is a linker lipid ester of aripiprazole for extended-release intramuscular (IM) injection. This multicenter, randomized, open-label study evaluated the pharmacokinetics (PK), relative bioavailability, and tolerability of a single IM deltoid or gluteal injection of aripiprazole lauroxil in adult subjects with chronic stable schizophrenia or schizoaffective disorder. Forty-six subjects were randomized 1:1 to aripiprazole lauroxil 441 mg IM in the deltoid or gluteal muscle. Samples were collected through 89 days post-dose to measure levels of aripiprazole lauroxil, N-hydroxymethyl aripiprazole, aripiprazole, and dehydro-aripiprazole. Forty-three (93.5%) subjects completed all study assessments; most were CYP2D6 extensive or immediate metabolizers (96%); two (4%) were poor metabolizers. The PK of aripiprazole following aripiprazole lauroxil was characterized by a steady rise in plasma concentrations (Tmax 44-50 days), a broad peak, and prolonged exposure attributable to the dissolution of aripiprazole lauroxil and formation rate-limited elimination of aripiprazole (t1/2=15.4-19.2 days). Deltoid vs. gluteal administration resulted in slightly higher Cmax aripiprazole concentrations [1.31 (1.02, 1.67); GMR 90% CI]; total exposure (AUCinf) was similar between sites of administration [0.84 (0.57, 1.24)]. N-hydroxymethyl-aripiprazole and dehydro-aripiprazole exposures were 10% and 33-36%, respectively, of aripiprazole exposure following aripiprazole lauroxil. The most common adverse events were injection site pain in 20 subjects (43.5%) and headache in 6 subjects (13.0%) of mild intensity occurring at a similar rate with deltoid and gluteal administration. Exposure ranges with deltoid and gluteal administration overlapped, suggesting that these sites may be used interchangeably. Despite a higher incidence of adverse events, deltoid muscle provides a more accessible injection site and could facilitate patient acceptance.

Lack of clinical pharmacodynamic and pharmacokinetic drug-drug interactions between warfarin and the antisense oligonucleotide mipomersen.

Mipomersen is a second-generation antisense oligonucleotide indicated as an adjunct therapy for homozygous familial hypercholesterolemia (HoFH). Warfarin is commonly prescribed for a variety of cardiac disorders in homozygous familial hypercholesterolemia population, and concurrent use of warfarin and mipomersen is likely. This open-label, single-sequence 2-period phase 1 study in healthy subjects evaluated the potential drug-drug interactions between mipomersen and warfarin. The subjects received a single oral 25 mg dose of warfarin alone on day 1, and after a 7-day washout period, received 200 mg mipomersen alone subcutaneously every other day on days 8-12, and received both concurrently on day 14. Coadministration of mipomersen did not change the pharmacodynamics (international normalized ratio, prothrombin time, and activated partial thromboplastin time) and pharmacokinetics (PK) of warfarin. There were no clinically significant changes in the PK of mipomersen with concurrent administration of warfarin. There were no events indicative of an increase in bleeding tendency when warfarin was coadministered with mipomersen, and the adverse event profile of mipomersen did not appear to be altered in combination with warfarin, as compared with that of the respective reference treatment. The combination of these 2 medications appeared to be safe and well tolerated. These results suggest that the dosage adjustment of warfarin or mipomersen is not expected to be necessary with coadministration.

Pharmacokinetics, safety and tolerability of mipomersen in healthy Japanese volunteers and comparison with Western subjects.

OBJECTIVES: To characterize the safety, tolerability, pharmacokinetics (PK) and dose proportionality of mipomersen after single subcutaneous (SC) administration to Japanese healthy subjects; and to compare the PK profiles of Japanese and Western subjects. METHODS: 20 healthy first-generation Japanese male subjects were enrolled into one of three treatment cohorts (50, 100 and 200 mg SC) in a dose-escalation design. Within each cohort, subjects were randomized in a 4 : 1 ratio to receive mipomersen or placebo. RESULTS: Mipomersen was absorbed rapidly after SC administration; median tmax varied between 2 and 3 hours. After reaching peak levels, plasma concentrations of mipomersen decayed multiphasically with an initial distribution t1/2 in several hours and a terminal t1/2 of 261 - 393 hours. Mean Cmax increased in a dose-linear manner while all mean AUC from time 0 to different cut points increased slightly more than dose proportionally. Although mean terminal t1/2 varied in the dose range tested, it did not show dose-dependence. The PK profiles of mipomersen in Japanese subjects are similar to those observed in Western subjects. A single SC dose of 50 mg, 100 mg and 200 mg mipomersen was well tolerated by male Japanese subjects. CONCLUSION: Single SC doses of 50 - 200 mg were safe and well tolerated when administered to Japanese subjects. Comparison of PK between Japanese and Western subjects does not support any need for dose adjustment in Japanese population in future clinical development.

Clofarabine-associated acute kidney injury in patients undergoing hematopoietic stem cell transplant.

Abstract We examined clofarabine pharmacokinetics and association with renal toxicity in 62 patients participating in a phase I-II study of clofarabine-melphalan-alemtuzumab conditioning for hematopoietic stem cell transplant (HSCT). Pharmacokinetic parameters, including clofarabine area under the concentration-time curve (AUC), maximum concentration and clearance, were measured, and patients were monitored for renal injury. All patients had normal pretreatment creatinine values, but over half (55%) experienced acute kidney injury (AKI) after clofarabine administration. Age was the strongest predictor of AKI, with older patients at greater risk (p = 0.002). Clofarabine AUC was higher in patients who developed AKI, and patients with the highest dose-normalized AUCs experienced the most severe grades of AKI (p = 0.01). Lower baseline renal function, even when normal, was associated with lower clofarabine clearance (p = 0.008). These data suggest that renal-adjustment of clofarabine dosing should be considered for older and at-risk patients even when renal function is ostensibly normal.