• Reviewed publically available PK and food-effect data from

oral immediate-release (IR) drug products with abuse-

deterrent (AD) technologies.

• Evaluated the partial extents of exposure (pAUCs) under

fed conditions as an additional BE metric.

• Utilized oxycodone PK data as an example supporting the

rationale of adding pAUC to current BE evaluation criteria,

through population PK modeling and simulation

Food Effects on Immediate-Release Abuse-Deterrent Opioids: Suggestions

for Comparative Bioavailability/Bioequivalence Regulatory RequirementsLOAN PHAM, ERIC KENDIG, VIEN LAI, MARC WILES, RUTH STEVENS

Camargo Pharmaceutical Services. 9825 Kenwood Road, Suite 203. Cincinnati, OH 45242

PURPOSE

METHODS

RESULTS

CONCLUSIONS• pAUC should be used as an additional BA/BE metric between

IR opioids (especially AD opioids) under fed conditions for

both 505(b)(2) and 505(j) pathways.

• In addition to classic BE criteria, pAUC0-4 may be considered

for IR oxycodone under fed conditions to evaluate the

potential for safety effects associated with lack of initial

analgesia.

• Population PK modeling and simulation of virtual BE trials

performed in this research can be applied for generic or

505(b)(2) drug products to identify the optimal pAUC

associated with early onset or duration of action

(efficacy/safety) of the drug. It should be noted that the unique

characteristics of each drug product should be considered for

optimal pAUC.

RESULTS

• Abuse-deterrent (AD) opioid dosage forms have produced

significant food effects on absorption—namely a

significantly delayed Tmax (longer than the labeled dosing

interval). Significant delays in Tmax correspond to delays in

onset of analgesia, which can in turn lead to dose stacking

and overdose/adverse effects.

• Current Comparative BA/BE Metrics for IR opioid

products: 90% CI values of geometric mean ratios of

Test/Reference Cmax and AUC (AUC0-t and AUC0-inf)

should fall within 80.00% -125.00%.

• We will recommend an additional BE metric, partial Area

Under the Curve (pAUC), for use to evaluate some AD

opioid drug products.

Combination of PK Parameters Probability1) Has a similar range of median Tmax

2) Has no lag time greater than 1 hour

3) BE on Cmax, AUClast, AUCinf

100%

Cmax, AUClast, AUCinf, and AUC0-6 100%

Cmax, AUClast, AUCinf, and AUC0-5 92%

Cmax, AUClast, AUCinf, and AUC0-4 86%

Cmax, AUClast, AUCinf, and AUC0-3 59%

Cmax, AUClast, AUCinf, and AUC0-2 20%

Cmax, AUClast, AUCinf, and AUC0-1 7%

There was an 86% chance of passing BE on AUC0-4. Cases that did

not pass BE on AUC0-4, despite having a median Tmax within 0.5 –

4.05 hours, had a Tmax distribution skewed to the right.

0 5 10 15 20 25 30 35 400

2

4

6

8

10

12

14

16

18

20

Time (hour)

Meth

ylp

henid

ate

(ng/m

L)

Monte Carlo Simulation of MPH Conc vs. Time Profiles in Plasma single 60-mg q24h

Step 3: Population PK Simulation of 100 virtual 2-way crossover BE trials (32 subjects/trial) between the hypothetical Test versus IR Reference (Roxicodone under Fed conditions)

Assumption: No individual has a lag time (Tlag) greater than 1 hour and the Test product has the same range of median Tmax as that of the Reference product (0.5 – 4.05 hr).

Randomly generated Test plasma concentration

profiles having median Tmax outside the range of

0.5 – 4.05 hours were excluded.

Step 1: Develop base and final covariate models

Step 2: Visual predictive check (VPC) of the

oxycodone population pharmacokinetic model

• No IR opioid oral drug products with clinical AD properties have been approved.

• Two IR products with AD properties have been developed: Oxaydo (Oxecta, NDA 202080) and Avridi (NDA

206830). These two 505(b)(2) NDAs referenced Roxicodone (NDA 021011) as the Listed Drug/BE comparator.

Oxaydo vs. Roxicodone under Fed Conditions

PK ParameterOxaydo, Fed vs

Roxicodone, Fed90% CI

AUC0-t (ng×hr/mL) 99.28% 94.43 – 104.37

AUC0-inf (ng×hr/mL) 99.44% 94.56 – 104.56

Cmax (ng/mL) 83.49% 76.66 – 90.93

Tmax (hr) Oxaydo, Fed Roxicodone, Fed

Median, range 3.00 (1.25 – 6.00) 1.00 (0.50 – 4.00)

PK ParameterAvridi, Fed vs

Roxicodone, Fed90% CI

AUC0-t (ng×hr/mL) 93.40% 91.1-95.9

AUC0-inf (ng×hr/mL) 93.50% 91.1-95.5

Cmax (ng/mL) 72.60% 68.4-77.0

Avridi vs. Roxicodone under Fed Conditions

Could well-controlled Phase 3 trials help?

Tmax (hr) Avridi, Fed Roxicodone, Fed

Median, range 4.00 (1.25 – 9.05) 1.50 (0.50 – 4.05)

When Oxaydo is administered with a high-fat meal, mean AUC

values increase by 21% and peak concentrations decrease by

14%. Food causes a delay in Tmax from 1.25 to 3.00 hours.

These changes in oxycodone pharmacokinetics are not

considered clinically relevant; therefore, Oxaydo can be taken

without regard to food.

Simulation of Repeated Administration of Avridi:

(Four Doses Every 30 Minutes or 1 Hour or 4 Hours

in the Fed State)

The simulation-based diagnostics of Roxicodone

concentrations (ng/mL) and time (hours; h),

n=1000. Lines represent simulated data; dashed

lines are 50th and 10th-90th quantiles; solid line is

5th-95th quantiles; open circles represent

observed concentrations; observations outside

the 90% prediction intervals = ~7%.

Avridi was not approved due to concerns that

delayed analgesia associated with a food effect

may lead to an increased risk of overdose.

Oxycodone Population PK Modeling and

Simulation

Probability of meeting 80.00% – 125.00% BE limits with

different pAUCs

Poster

Number

04M0100