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Pharmacokinetics of Long-Acting Aqueous Nano-/Microsuspensions After Intramuscular Administration in Different Animal Species and Humans—a Review

  • Review Article
  • Perspectives on clinical drug development of Long-Acting Injectables
  • Published:
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Abstract

Formulating aqueous suspensions is an attractive strategy to incorporate poorly water-soluble drugs, where the drug release can be tailored to maintain desired release profiles of several weeks to months after parenteral (i.e., intramuscular or subcutaneous) administration. A sustained drug release can be desirable to combat chronic diseases by overcoming pill fatigue of a daily oral intake, hence, improving patient compliance. Although the marketed aqueous suspensions for intramuscular injection efficiently relieve the daily pill burden in chronic diseases, the exact drug release mechanisms remain to be fully unraveled. The in vivo drug release and subsequent absorption to the systemic circulation are influenced by a plethora of variables, resulting in a complex in vivo behavior of aqueous suspensions after intramuscular administration. A better understanding of the factors influencing the in vivo performance of aqueous suspensions could advance their drug development. An overview of the potential influential variables on the drug release after intramuscular injection of aqueous suspensions is provided with, where possible, available pharmacokinetic parameters in humans or other species derived from literature, patents, and clinical trials. These variables can be categorized into drug substance and formulation properties, administration site properties, and the host response towards drug particles. Based on the findings, the most critical factors are particle size, dose level, stabilizing excipient, drug lipophilicity, gender, body mass index, and host response.

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Abbreviations

APZ:

Aripiprazole

AUC:

Area under the curve

AUC∞ :

Area under the curve from time zero to infinity

AUClast :

Area under the curve from time zero to time of last measurement

AUCtau :

Area under the curve during one dosing interval

ARV:

Antiretrovirals

BDQ:

Bedaquiline

BMI:

Body mass index

CAB:

Cabotegravir

C max :

Peak plasma concentration

CI:

Confidence interval

DTG:

Dolutegravir

D V50 :

Volume median diameter of particle size distribution

D V90 :

90% Volume diameter of particle size distribution

E2-Cyp:

Estradiol cypionate

EV:

Entecavir

EV-P:

Entecavir-3-palmitate

F:

Female

FDA:

Food and Drug Administration

IM:

Intramuscular

LAI:

Long-acting injectable

λZ :

Terminal rate constant

LB:

Levonorgestrel butanoate

LogP:

Partition coefficient

M:

Male

M3RPV:

Myristoyl rilpivirine

MDTG:

Myristoyl dolutegravir

ME:

Mestranol

MENT:

7α-Methyl-19-nortestosterone

MP acetate:

Methylprednisolone acetate

MPA:

Medroxyprogesterone acetate

MW:

Molecular weight

Na-CMC:

Sodium carboxymethyl cellulose

NET:

Norethindrone

NCAB:

Nanoformulated cabotegravir

NM2CAB:

Nanoformulated stearoyl cabotegravir

NMCAB:

Nanoformulated myristoyl cabotegravir

NRPV:

Nanoformulated rilpivirine

OLZ:

Olanzapine

P188:

Poloxamer 188

P338:

Poloxamer 338

P407:

Poloxamer 407

PAL:

Paliperidone

PBS:

Phosphate buffered saline

PEG:

Polyethylene glycol

PK:

Pharmacokinetics

PP:

Paliperidone palmitate

PP1M:

Paliperidone palmitate 1 month

PP3M:

Paliperidone palmitate 3 months

PP6M:

Paliperidone palmitate 6 months

PS20:

Polysorbate 20

PS80:

Polysorbate 80

RPV:

Rilpivirine

SC:

Subcutaneous

SD:

Standard deviation

Span 20:

Sorbitan monolaurate

Span 40:

Sorbitan monopalmitate

t 1/2 :

Half-life

T max :

Time of maximum concentration observed

TPGS:

D-alpha-tocopheryl polyethylene glycol 1000 succinate

TU:

Testosterone undecanoate

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The authors wish to thank Bram Schroyen for the input and advice.

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  1. Ghent University, Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ottergemsesteenweg 460, B-9000, Ghent, Belgium

    Vy Thi Thanh Nguyen & An Vermeulen

  2. Pharmaceutical Product Development & Supply, Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Antwerp, Belgium

    Nicolas Darville

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Nguyen, V.T.T., Darville, N. & Vermeulen, A. Pharmacokinetics of Long-Acting Aqueous Nano-/Microsuspensions After Intramuscular Administration in Different Animal Species and Humans—a Review. AAPS J 25, 4 (2023). https://doi.org/10.1208/s12248-022-00771-5

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