Pharmacokinetics and in vivo drug release rates in liposomal nanocarrier development

doi:10.1002/jps.21358

Journal of Pharmaceutical Sciences

Volume 97, Issue 11, November 2008, Pages 4696-4740

https://doi.org/10.1002/jps.21358 Get rights and content

Abstract

Liposomes represent a widely varied and malleable class of drug carriers generally characterized by the presence of one or more amphiphile bilayers enclosing an interior aqueous space. Thus, the pharmacological profile of a particular liposomal drug formulation is a function not only of the properties of the encapsulated drug, but to a significant extent of the pharmacokinetics, biodistribution, and drug release rates of the individual carrier. Various physicochemical properties of the liposomal carriers, the drug encapsulation and retention strategies utilized, and the properties of the drugs chosen for encapsulation, all play an important role in determining the effectiveness of a particular liposomal drug. These properties should be carefully tailored to the specific drug, and to the application for which the therapeutic is being designed. Liposomal carriers are also amenable to additional modifications, including the conjugation of targeting ligands or environment-sensitive triggers for increasing the bioavailability of the drug specifically at the site of disease. This review describes the rationale for selecting optimal strategies of liposomal drug formulations with respect to drug encapsulation, retention, and release, and how these strategies can be applied to maximize therapeutic benefit in vivo.

Section snippets

INTRODUCTION

Liposomes constitute a class of microparticulate or nanoparticulate drug carriers generally characterized by the presence of one or more amphiphile bilayers enclosing an interior aqueous space. Liposomes have been used to increase the therapeutic index of a wide range of antineoplastic agents.¹ This has primarily been accomplished by improving the pharmacokinetic profile or allowing for site-specific drug delivery to solid tumors. For example, pegylated liposomal doxorubicin (PLD; Doxil®,

FACTORS THAT INFLUENCE THE PHARMACOKINETICS OF LIPOSOMES

There are a wide range of factors that influence the pharmacokinetics and biodistribution of liposomal nanocarriers. The clearance of a liposome-associated drug from the blood is dependent on: (1) the rate of clearance of the liposomal carrier itself, (2) the rate of disassociation of the complexed, entrapped, or lipid membrane-solubilized drug from the carrier, and the (3) rate of clearance and metabolism of free drug upon its release. The pharmacokinetics of the actual liposomal carriers have

CONTROL OF IN VIVO DRUG RELEASE RATES

The rate of in vivo drug release is an extremely important parameter since it can influence the rate of clearance of the drug from the general circulation, the bioavailability and thus activity of the drug at its site of action, the targetability of the drug, and the observed toxicities.¹^, ³¹ Many groups have routinely attempted to demonstrate liposome stability using in vitro incubations in the presence of saline or plasma. Although these somewhat useful preliminary measures of formulation

RELATIONSHIP OF PHARMACOKINETICS AND DRUG RELEASE RATES ON TOXICITY OF LIPOSOMAL DRUGS

The relationship relating pharmacokinetics, bioavailability, and toxicity is not as simple as is often suggested. The general dogma is that encapsulation and delivery of therapeutic agents in liposomes results in site-specific delivery of the therapeutic agent to the site of disease, reducing exposure to healthy tissues and increasing the exposure at the site of disease. The logical conclusion that is routinely drawn is that this combination of effects results in a decrease in toxicity for the

EFFECT OF DRUG RELEASE RATES ON ANTITUMOR EFFICACY

Liposomes that displayed longer circulation lifetimes have typically displayed greater antitumor efficacy in various tumor models.¹^, ²^, ³¹ However, claims of superiority based on pharmacokinetics of the carrier alone must be carefully evaluated since often the differences between the formulations dictate both a change in the pharmacokinetics of the carrier as well as drug retention.217., 218., 219. Although liposomes that display dramatic differences in pharmacokinetics generally show superior

TRIGGERED DELIVERY OF ENCAPSULATED THERAPEUTICS

Triggered delivery of liposomal therapeutics can result from either a stimulus-induced increase in delivery of the liposomal carrier itself to the site of disease or as a result of increased drug release from the carrier. In some instances a particular trigger may be able to induce both increased localization of the liposomal carrier and increased drug release at the site of disease. Ideally, an encapsulated drug would be quantitatively retained in the carrier until the carrier lodges in the

SPECIFIC DELIVERY CHALLENGES FOR NUCLEIC ACIDS

Nucleic acid based therapeutics are seen as a strategy for treating diseases at the level of genetic information transfer. The efficient delivery of these molecules to sites of their intended action remains a major obstacle, and of the available choices of delivery vehicles, nonviral lipid based carriers occupy a prominent place. The ability of a liposome to carry a functional nucleic acid into a cell was demonstrated in the early days of liposome pharmacology.²⁷⁹^, ²⁸⁰ However, there is still a

SUMMARY

Significant advances have been made in recent years in controlling the pharmacokinetics and drug release profiles of weakly basic amphiphilic drugs in liposomal carriers. However, there still remains a fair degree of engineering to tailor a specific chemical entity to its carrier even within this class of drugs. Nonetheless, there are currently multiple examples of successfully formulated drugs from this class that are either already approved for use in oncology applications, or are in clinical

Acknowledgements

Much of the work reviewed within was supported by a variety of mechanisms, including a New Investigator Award (Daryl Drummond) from the California Breast Cancer Research Program of the University of California (Grant Number 7KB-0066), as well as grants from the National Cancer Institute Specialized Programs of Research Excellence (SPORE) in Breast Cancer (P50-CA58207) and Brain Tumors (P50-CA097257).

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ReviewsPharmacokinetics and in vivo drug release rates in liposomal nanocarrier development

Abstract

Section snippets

INTRODUCTION

FACTORS THAT INFLUENCE THE PHARMACOKINETICS OF LIPOSOMES

CONTROL OF IN VIVO DRUG RELEASE RATES

RELATIONSHIP OF PHARMACOKINETICS AND DRUG RELEASE RATES ON TOXICITY OF LIPOSOMAL DRUGS

EFFECT OF DRUG RELEASE RATES ON ANTITUMOR EFFICACY

TRIGGERED DELIVERY OF ENCAPSULATED THERAPEUTICS

SPECIFIC DELIVERY CHALLENGES FOR NUCLEIC ACIDS

SUMMARY

Acknowledgements

Semin Oncol

Gynecol Oncol

Clin Lymphoma Myeloma

J Control Release

Anal Biochem

Lung Cancer

Prog Lipid Res

Adv Drug Deliv Rev

J Control Release

J Control Release

J Control Release

Biochim Biophys Acta

Life Sci

Biochim Biophys Acta

Biochim Biophys Acta

Biochim Biophys Acta

Biochim Biophys Acta

Biochim Biophys Acta

Biophys J

Biophys J

Biochim Biophys Acta

Biochim Biophys Acta

J Biol Chem

Biochim Biophys Acta

Biochim Biophys Acta

Biochim Biophys Acta

Biochim Biophys Acta

Biochim Biophys Acta

J Control Release

J Control Release

Ann Oncol

Biochim Biophys Acta

Biochim Biophys Acta

Adv Drug Deliv Rev

Biochim Biophys Acta

Prog Lipid Res

Adv Drug Deliv Rev

Int Immunopharmacol

J Control Release

Brain Res

Exp Neurol

J Neurosci Methods

Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors

Pharmacol Rev

Pharmacokinetics of pegylated liposomal Doxorubicin: Review of animal and human studies

Clin Pharmacokinet

Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: Results of a randomized phase III clinical trial

J Clin Oncol

Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma

J Clin Oncol

Phase III data on Caelyx in ovarian cancer

Eur J Cancer

Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: A Phase III multicenter randomized trial

Cancer

Liposomal and nonliposomal drug pharmacokinetics after administration of liposome-encapsulated vincristine and their contribution to drug tissue distribution properties

J Pharmacol Exp Ther

Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy

Cancer Res

Reviews
Pharmacokinetics and in vivo drug release rates in liposomal nanocarrier development