Bioavailability and pharmacokinetic profile of a newly-developed twice-a-day sustained-release paracetamol formulation

2017

Self Cite

Acetaminophen (paracetamol) is a first‐line treatment for mild and moderate pain. A twice‐daily sustained‐release (SR) formulation may be more convenient for chronic users than standard immediate‐release (IR) acetaminophen. This randomized, 3‐way crossover study evaluated pharmacokinetics and safety of single‐dose 1500‐ and 2000‐mg SR acetaminophen formulations and 2 doses of IR acetaminophen 1000 mg given 6 hours apart in healthy adults (n = 14). Primary outcome was time that plasma acetaminophen concentration was ≥4 μg/mL (TC≥4μg/mL). Key secondary outcomes were area under the plasma concentration–time curve (AUC) from time 0 to time t, when plasma acetaminophen was detectable (AUC0–t), AUC from 0 to infinity (AUC0–inf), and maximum plasma acetaminophen concentration (Cmax). TC≥4μg/mL from 2000‐mg SR acetaminophen was similar to that from 2 doses of IR acetaminophen, whereas TC≥4μg/mL for 1500‐mg SR acetaminophen was significantly shorter than that for IR acetaminophen (P = .004). The extent of acetaminophen absorption from 2000‐mg SR and 2 doses of the IR formulation was similar and within bioequivalence limits with regard to AUC0–12, AUC0–t, and AUC0–inf. The extent of acetaminophen absorption from 1500‐mg SR was significantly lower than that from IR acetaminophen. The 2000‐mg SR represents a potential candidate formulation for 12‐hour dosing with acetaminophen.

Section: Discussionsupporting

confidence: 72%

Evaluation of a 12‐Hour Sustained‐Release Acetaminophen (Paracetamol) Formulation: A Randomized, 3‐Way Crossover Pharmacokinetic and Safety Study in Healthy Volunteers

Yue

Collaku

2017

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“…We have since conducted 2 single‐dose PK studies demonstrating that the bilayer SR tablet (2 × 1000 mg) had comparable bioavailability but greater SR characteristics compared with IR (2 × 500 mg) and ER (2 × 665 mg) APAP formulations and maintained plasma concentrations at or above 4 μg/mL for a longer duration than either IR or ER APAP …”

Section: Discussionmentioning

confidence: 99%

“…A series of 4 investigational SR APAP formulations was designed to allow twice‐daily dosing. These included a bilayer SR tablet, 2 single‐layer SR tablets (referred to hereafter as single‐layer SR APAP #1 and single‐layer SR APAP #2, which differed with regard to the excipients used in the formulations), and an enteric‐coated SR tablet given in combination with a fast‐disintegrating (FD) IR formulation (Table ). The primary objective of this proof‐of‐principle study was to evaluate the duration of time that plasma APAP levels remained above a threshold of 4 μg/mL (T C>4μg/mL ) with 4 new SR APAP formulations compared with 2 standard 1000‐mg doses of IR APAP taken 6 hours apart.…”

Section: Study Formulationsmentioning

confidence: 99%

Selection of 12‐Hour Sustained‐Release Acetaminophen (Paracetamol) Formulation Through Comparison of Pharmacokinetic Profiles of 4 Sustained‐Release Prototype Formulations and Standard Acetaminophen Formulation: An Open‐Label, Randomized, Proof‐of‐Principle Pharmacokinetic Study

Yue

2017

Self Cite

Acetaminophen (APAP; paracetamol), a widely used analgesic and antipyretic, is available in modified‐release and immediate‐release (IR) formulations requiring 3‐ or 4‐times‐daily dosing. This phase 1 open‐label crossover study compared pharmacokinetic profiles of single 2000‐mg doses of 4 different sustained‐release (SR) formulations of APAP (designed to allow twice‐daily dosing) against two 1000‐mg doses (taken 6 hours apart) of standard IR APAP in 14 healthy volunteers. The primary end point was duration of time that plasma APAP concentration exceeded a plasma concentration (TC) of 4 μg/mL. Of the 4 SR APAP formulations studied, a single 2000‐mg dose of a bilayer SR formulation had the longest mean TC>4μg/mL (8.1 hours), similar to that of 2 doses of IR APAP (8.3 hours). Mean TC>4μg/mL was 7.3 hours with a single‐layer SR APAP, 7.5 hours with another single‐layer SR APAP formulation using a different excipient, and 7.1 hours with an enteric‐coated SR APAP coupled with a fast‐dissolving IR APAP. Secondary pharmacokinetic analyses showed a similar extent of absorption and lower peak concentration for the bilayer SR formulation compared with IR APAP. Adverse events were all mild. Based on these results, the bilayer SR APAP formulation was selected for further development.

“…The new SR paracetamol has a pharmacokinetic (PK) profile that includes prolonged exposure, which allows the number of daily doses required to be further reduced to only 2. This formulation, developed with the aid of an in vivo modeling and simulation technique, is a white film‐coated, bilayered tablet consisting of a layer of IR paracetamol (10%) and a layer of SR paracetamol (90%) that contains hydroxypropyl methycellulose polymer . Two tablets (2 × 1000 mg) can be taken twice daily, for a maximum of 4000 mg.…”

mentioning

confidence: 99%

“…We previously reported the single‐dose PK profile of the new SR paracetamol compared with currently marketed ER and IR paracetamol formulations in both fasted and fed states . SR paracetamol was well absorbed, with >90% relative bioavailability compared with the IR and ER products.…”

mentioning

confidence: 99%

Bioequivalence and Safety of Twice‐Daily Sustained‐Release Paracetamol (Acetaminophen) Compared With 3‐ and 4‐Times‐Daily Paracetamol: A Repeat‐Dose, Crossover Pharmacokinetic Study in Healthy Volunteers

Collaku

2017

Self Cite

Twice‐daily sustained‐release (SR) paracetamol (acetaminophen) offers convenient administration to chronic users. This study investigated at steady state (during the last 24 hours of a 3‐day dosing period) the pharmacokinetics, bioequivalence, and safety of twice‐daily SR paracetamol compared with extended‐release (ER) and immediate‐release (IR) paracetamol. In this open‐label, randomized, multidose, 3‐way crossover study, 28 healthy subjects received paracetamol SR (2 × 1000 mg twice daily), ER (2 × 665 mg 3 times daily), and IR (2 × 500 mg 4 times daily). At steady state, twice‐daily SR paracetamol was bioequivalent to ER and IR paracetamol. The 90% confidence intervals for the ratios of geometric means were within the acceptance interval for SR/ER paracetamol (AUC0–t, 0.973–1.033; AUC0–24, 0.974–1.034; AUC0–∞, 0.948–1.011; Cmax, 1.082–1.212; Cav, 1.011–1.106) and SR/IR paracetamol (AUC0–t, 0.969–1.029; AUC0–24, 0.968–1.027; AUC0–∞, 0.963–1.026; Cmax, 0.902–1.010; Cav, 1.004–1.098). Given twice daily, the SR formulation demonstrated SR properties as expected. Mean time at or above a 4 μg/mL plasma concentration of paracetamol from 2 daily doses of the SR formulation was significantly longer than that from 4 daily doses of IR paracetamol. SR formulation also had a greater Tmax, a longer half‐life, and lower Cmin compared with ER and IR paracetamol. All formulations were well tolerated.