Application of Quantitative Clinical Pharmacology in the ...

[Pages:36]Application of Quantitative Clinical Pharmacology in the Development of Long-Acting Injectable (LAI) Drug Products

PQRI 2021 Webinar April 08, 2021

Liang Zhao, Ph.D.

Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs |CDER | U.S. FDA

Disclaimer

This presentation reflects the views of the presenter and should not be construed to

represent FDA's views or policies.



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? Poor adherence to prescribed medications significantly impacts the U.S. health care system.

? Given the human and financial consequences, the development of strategies for improving adherence to prescribed medications is imperative.

? Long-acting injectable (LAI) drug products are one of several interventions for improving patient adherence to

prescription medications.



Sharan et al. 2021, CPDD 10(3): 220-228

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Long-Acting Injectable Drug Products

? Long-acting injectable (LAI) drug products are formulated to achieve extended drug release action from days to years when administered via intramuscular, subcutaneous, intravitreal, or other routes.

? These products can help improve patient compliance with a better therapeutic option to treat patients who adhere poorly to frequently administered medication.



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Examples of FDA Approved Long-Acting Injectable Drug Products and Approved ANDAs

Trade Names

Ingredient

ABILIFY MAINTENA KIT

ARIPIPRAZOLE

ARISTADA

ARIPIPRAZOLE LAUROXIL

ARISTADA INITIO KIT

ARIPIPRAZOLE LAUROXIL

SUBLOCADE

BUPRENORPHINE

PROBUPHINE

BUPRENORPHINE HYDROCHLORIDE

CABENUVA KIT

CABOTEGRAVIR; RILPIVIRINE

ATRIDOX

DOXYCYCLINE HYCLATE

BYDUREON BCISE

EXENATIDE

BYDUREON...BYDUREON PEN

EXENATIDE SYNTHETIC

YUTIQ

FLUOCINOLONE ACETONIDE

ZOLADEX

GOSERELIN ACETATE

SUSTOL

GRANISETRON

LUPRON DEPOT...LUPRON DEPOT-PED

LEUPROLIDE ACETATE

ELIGARD

LEUPROLIDE ACETATE

LUPANETA PACK

LEUPROLIDE ACETATE; NORETHINDRONE ACETATE

DEPO-PROVERA

MEDROXYPROGESTERONE ACETATE

DEPO-SUBQ PROVERA 104

MEDROXYPROGESTERONE ACETATE

SINUVA

MOMETASONE FUROATE

VIVITROL

NALTREXONE

SANDOSTATIN LAR

OCTREOTIDE ACETATE

ZYPREXA RELPREVV

OLANZAPINE PAMOATE

INVEGA SUSTENNA

PALIPERIDONE PALMITATE

INVEGA TRINZA

PALIPERIDONE PALMITATE

SIGNIFOR LAR KIT

PASIREOTIDE PAMOATE

PERSERIS KIT

RISPERIDONE

RISPERDAL CONSTA

RISPERIDONE

XYOSTED (AUTOINJECTOR)

TESTOSTERONE ENANTHATE

ZILRETTA

TRIAMCINOLONE ACETONIDE

TRIPTODUR KIT

TRIPTORELIN PAMOATE

TRELSTAR

TRIPTORELIN PAMOATE

Indication Schizophrenia; bipolar I disorder

Schizophrenia Schizophrenia Opioid use disorder Opioid Dependence HIV-1 treatment Chronic adult periodontitis Improve glycemic control in type II diabetes Improve glycemic control in type II diabetes Chronic non-infectious uveitis affecting the posterior segment of the eye carcinoma of prostate, endometriosis, breast cancer Antiemetics for prevention of acute and delayed nausea and vomiting with chemotherapy Endometriosis, Fibroids, Advanced prostrate cancer; children with central precocious puberty Palliative treatment of advanced prostate cancer Endometriosis Prevention of Pregnancy Prevention of pregnancy, endometriosis-associated pain Nasal polyps who had ethmoid surgery Alcohol/Opioid Dependence Acromegaly, Carcinoid Tumors and Vasoactive Intestinal Peptide secreting tumors Schizophrenia Schizophrenia, schizoaffective disorder, mood stabilizers or antidepressants Schizophrenia Acromegaly, Cushing's Disease Schizophrenia Schizophrenia, Bipolar I Disorder Testosterone replacement therapy Osteoarthritis pain of the knee precocious puberty Advanced prostrate cancer

Dose Frequency

Approved Generic

Monthly

0

Monthly, 6 weeks, 2 months

0

One time

0

Monthly

0

one time (6 months)

0

Monthly

0

1 week

0

Weekly

0

Weekly

0

36 months (one time)

0

Monthly (4 weeks)

0

Weekly

0

1,3,4,6 months

0

1,3,4,6 months

0

Monthly

0

3 months

1

3 months

0

3 months (one time)

0

Monthly (4 weeks)

0

Monthly (4 weeks)

0

2, 4 weeks

0

Monthly

0

3 months

0

4 weeks

0

Monthly

0

2 weeks

0

weekly

0

3 months (one time)

0

24 weeks

0

4/12/24 weeks

0



Drugs@FDA

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Long-Acting Injectable Pharmacokinetics

t1/2=23 hr Washout (>5 t1/2)

t1/2=40d Washout (>5 t1/2)

? LAI pharmacokinetics (PK) are characterized by a rate of drug absorption that is slower than their rate of elimination; hence, they exhibit flipflop kinetics.

? In these products, the terminal phase of the drug profile reflects the rate of absorption, rather than the rate of elimination, as is usually observed in classical linear drug PK.

? The long terminal phase of these products poses several challenges for the development of new versions, as well as generic copies.

Figure adapted from ACCP presentation by Mats Karlsson on 9/19/2019

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Challenges in LAI Product Development and Lifecycle Management

? Long apparent half-life:

? Longer time to reach steady state

? Longer wash out time

? Longer duration for bioequivalence (BE) studies

? Challenging to propose relevant dosing scenarios, e.g.,

? Impact of early, delayed or missed doses

? High drop out rate

? Not practical to perform a singledose crossover BE study



? Switching between formulations

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Opportunities for Modeling and Simulation in LAI Product Development

? Dosing regimen

? Justification for dosing recommendation for missed doses

? Impact of early, delayed, or missed doses

? Dose adjustment for special population

? Bridging results from previous studies/application

? Reducing cost, time; increasing efficiency



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