Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia: a literature review of pharmaceutical and clinical aspects

Abstract

Objectives

The rate of dermal toxicity has been shown to increase in patients receiving pegylated liposomal doxorubicin (PLD), particularly palmar-plantar erythrodysesthesia (PPE). However, it is difficult to diagnose and treat PLD-related PPE due to its delayed dermal performance, unclear pathogenetic mechanism, and the lack of specific preventive measures. The aim of this study was to provide potential management strategies for PPE associated with PLD.

Methods

The current article reviews the available data regarding the pharmacological and clinical aspects of PLD, including the formulation and pharmacokinetics of PLD, dose and schedule contribution to PPE, concomitant drugs affecting skin toxicity of PLD, the pathogenesis of PPE, and preventive measures and treatment of PLD-related PPE.

Results

The long circulation structure of polyethylene glycol liposomes may be one of the reasons for PPE. PLD has radically different pharmacokinetic characteristics, including prolonged blood circulation time, decreased body distribution volume, and slow clearance. Altering the schedules and doses of PLD or combining it with platinum compounds can optimise clinical efficacy and minimise the occurrence of PPE. Doses of 150–200 mg of pyridoxine daily have been widely used for the prevention and treatment of PPE. Regional cooling and plasma filtration have been used for PPE prophylaxis.

Conclusions

To date, the mechanism of PPE induced by PLD remains unclear, and no complete preventive medication has been established. Further research and prospective randomised studies are needed to understand the management options in PLD-related PPE.

Introduction

Pegylated (polyethylene glycol-coated) liposomal doxorubicin (PLD) was approved for clinical use by the US Food and Drug Administration (FDA) in November 1994 and became the first de facto cancer nanomedicine.¹ It is indicated for HIV-related Kaposi’s sarcoma, advanced ovarian cancer, metastatic breast cancer, and multiple myeloma. The FDA-approved dose of PLD is 50 mg/m² every 4 weeks.² Despite two decades of clinical use, this peculiar reformulation of doxorubicin has revealed many unique properties and unexpected clinical responses.³ As of today, PLD is an active agent for gynaecologic malignancies.^{4 5}

Conventional doxorubicin (DOX) has been shown to have significant therapeutic activity in the treatment of various malignant tumours.⁶ Its use is limited by a problematic toxicity profile, including myelosuppression and cumulative cardiotoxicity. PLD alters the pharmacokinetics and biodistribution profile of DOX. Liposomal formulation, in turn, reduces the toxicity associated with DOX, particularly cardiac toxicity.⁷ However, compared with the clinical manifestations of DOX, the dermal toxicity of PLD has been shown to increase. Palmar-plantar erythrodysesthesia (PPE) is a distinctive dermatologic toxic reaction associated with PLD. PPE typically presents with dysesthesia and tingling in the hands and feet. The symptoms may progress into blistering desquamation, crusting, ulceration, and epidermal necrosis. Dysesthesias and erythema may occur on several other body surface, especially in areas where pressure or increased warmth occur, such as on the buttocks, groin, under pendulous breasts, and in the axillae.⁸ PPE can be uncomfortable and can interfere with the ability to carry out normal activities. It is difficult to diagnose PLD-related PPE due to its delayed dermal performance, unclear pathogenetic mechanism, and the lack of specific histopathological characteristics.

This article reviews the available data regarding the pharmacological and clinical aspects of PLD, including the formulation and pharmacokinetics, the aetiology, and preventive measures and treatment of PLD-related PPE. The aim of this study was to provide potential management strategies for PPE associated with PLD.

Pharmacy structure and specific pharmacokinetics in vivo of PLD

PPE is the distinctive dermal toxicity of PLD.⁸ Clinical data from one study showed that 77.4% of PPE occurred during the first three cycles of chemotherapy, and the incidence was higher after multiple injections.^{9 10} The occurrence of PPE and a higher exposure to PLD were independently shown to lead to a prolonged progression-free survival.¹¹ But when PPE occurred, it caused blistering and peeling, ulcers, and epidermal necrosis without a delay in the next chemotherapy cycle or a dose reduction.

Yokomichi et al studied the effects of DOX and PLD on Sprague Dawley rats as an animal model.¹² The results showed that only PLD induced PPE, suggesting that the long circulation structure of polyethylene glycol liposomes may be one of the reasons for PPE. Understanding the formulation and pharmacokinetic implications of PLD is important for clinicians to prevent the adverse effects of PPE.

PLD is an ellipsoidal liposome with a particle size of about 80–90 nm (figure 1). The liposome bilayer structure in PLD is composed of hydrogenated soy phosphatidylcholine, cholesterol, and polyethylene glycol (PEG)-modified phosphatidylethanolamine with a molar ratio of about 55:45:5. DOX is inside the liposomes, and PEG coating is outside the liposomes.¹³ Researchers have reported on the physicochemical characterisation of PLD liposomes using electron microscopy and X-ray diffraction. One study using X-ray scattering provided a high-resolution structural analysis of PLD.¹⁴ The results showed that DOX existed in the ellipsoidal liposomes in the form of rod-like doxorubicin sulfate crystals with an average particle size of 8–9 nm. The crystal structure suggested little or no interaction between DOX and the lipid bilayer, which was consistent with the actual results. In addition, the PEG layer was asymmetrically distributed inside and outside the liposome, and there were more PEG chains in the outer layer. Within the liposome, the PEG chain was mainly in the mushroom shape, whereas in the outer layer, the PEG chain was in the long shape from the mushroom shape to the brush shape, with an average length of about 4.3 nm. The PEG layer provided a highly hydrophilic, protective, and flexible protective layer for the liposomes, preventing them from being detected and swallowed by the mononuclear phagocyte system (MPS).¹⁵

Figure 1.

Schematic drawing of a liposome.

The structural composition of the liposome membrane, the physical state of the liposome, the internal environment, the particle size, the surface structural modification of the liposome, and the surface charge all lead to PLD with unique pharmacological characteristics and clinical manifestations.⁷ Moreover, the pharmacokinetic characteristics of PLD in the human body have been shown to be completely different from those of DOX, which mainly manifests as prolonged blood circulation time, decreased body distribution volume, and slow clearance.

The pegylation of liposomes protects liposomes from the MPS uptake.¹⁵ Pegylated liposomes, in comparison to non-pegylated ones, have been shown to have a much longer half-life (T_1/2). In human pharmacokinetics, the T_1/2 of DOX is between 20 and 30 hours, whereas the T_1/2 of PLD is between 50 and 80 hours or even longer.^{7 16} One study provided evidence for a correlation of T_1/2 with PPE. Patients with T_1/2 >80 hours had a significantly higher risk of severe PPE.¹⁷ Moreover, PLD exists as a parent drug in plasma, and its metabolites are difficult to detect in plasma. However, a large number of metabolites have been found in urine, suggesting that the excretion of PLD metabolites is faster than its production, thus reducing the accumulation of metabolites in plasma.¹⁸ The high concentration and continuous circulation of PLD in plasma also result in a large area under the curve (AUC) value of the drug, ≥1000 times as large as the AUC value of DOX of the same dose. Nearly all circulating drugs in PLD are in the form of liposomes and therefore cannot be directly bio-utilized, which explains the difference between high blood concentrations and relatively mild toxicity revealed in studies.^{18 19} When patients with Kaposi sarcoma in the low-dose group (20 mg/m²) were treated with PLD compared with the standard dose (50 mg/m²), the following observations were made. At a standard dose, the elimination half-life was longer than expected, and the clearance rate was lower compared with the low-dose group, suggesting dose-dependent saturation of PLD clearance.²⁰ Suzuki et al conducted a preclinical study and found that repeated injection of PLD into miniature pigs with a concentration <2 mg/m² showed a phenomenon of accelerated blood clearance (ABC), whereas no such phenomenon was observed at 20 mg/m². The study also showed that the degree of induction of ABC was related to the first dose of PLD, and a high dose of PLD reduced ABC.²¹

The enhanced permeability and retention effect (EPR) is an important characteristic of solid tumour tissue and an important theoretical basis for the targeted treatment of tumours with nanoparticles (figure 2).²² Multiple studies based on confocal laser scanning microscopy have analysed the distribution of PLD and DOX in subcutaneous tumorigenesis mouse models, and the results showed that the accumulation of PLD in tumour sites was five times as much as that of DOX.²³ It is worth mentioning that hepatic clearance tends to be saturated when PLD dose increases. However, tumour tissue uptake is unsaturated, leading to a proportional increase in the accumulation of liposomes in tumour tissue to the concentration of drugs in plasma. This is the main reason why the distribution concentration of PLD in tumour tissues is better than that of DOX.²⁴ Another key pharmacologic question about PLD is how doxorubicin is released from liposomes in the tumour microenvironment and becomes absorbed by the cells, since pegylated liposomes are rarely absorbed by the cells and are mostly distributed in tumour interstitial fluid. In recent years, a novel mechanism for the release of DOX by liposomes in vivo has been proposed.²⁵ One study showed that ammonia promoted the PLD release of doxorubicin in vitro, which suggested that the tumour microenvironment generated sufficient ammonia to induce drug release from liposomes through the glutaminolysis pathway, thus improving the therapeutic effect of PLD.

Figure 2.

In vivo normal tissue and tumour tissue delivery of PLD; liposomes extravasate into the tumour interstitial fluid and release doxorubicin, which freely diffuses into cells.

Clinical studies have also found that patients with PPE have a larger AUC and are more sensitive to PLD treatment, making the drug treatment effect better. Studies have shown that an increase in the AUC value means an increase in PLD exposure, and the incidence of PPE gradually increases.^{11 26} This may be because the total exposure to PLD is associated with toxicity. This is because the repeated administration of PLD may lead to increased drug exposure.²⁷ The MPS plays a key role in preclinical and clinical pharmacokinetics of PLD. As mentioned above, PLD exists in clearance saturation at higher doses. In subsequent studies, it was found that during repeated cycles of chemotherapy, PLD clearance appeared to decrease in subsequent cycles, which may have stemmed from the decline of MPS functionality.²⁸ After PLD treatment, the number of pre-cycle monocytes decreased, and the PLD clearance was also decreased, suggesting that the toxicity of doxorubicin to the MPS reduces the clearance capacity of the MPS to PLD—that is, between the first and third cycles of repeated chemotherapy in the human body, repeated drug administration may lead to a decrease in the PLD clearance. When the first cycle of chemotherapy was compared with the third cycle, the AUC per mg dose of PLD increased by >40%, indicating slight damage to the MPS, which was not obvious in the first cycle but became obvious in the subsequent cycle, and PLD-related toxicity increased with the decrease in clearance. Further study of the relationship between these patient factors, PLD pharmacokinetics, and clinical outcomes (efficacy and toxicity) may aid in developing strategies for optimising PLD treatment.

Dose and schedule contribution to PPE

Preclinical and clinical data indicate that changing the interval and/or dose intensity of PLD administration can reduce the incidence or severity of PPE. Studies by Ranson et al and Lyass et al evaluated the effects of different doses and dosing intervals on the incidence of PPE after PLD use in breast cancer patients.^{29 30} The results showed that shorter intervals between doses increased the skin toxicity of PLD. This was related to the decline of MPS functionality, which led to a decrease in PLD clearance in each subsequent cycle. Moreover, patients with recurrent ovarian cancer were assessed with PLD 20 mg/m² every 14 days and 30 mg/m² every 21 days.^{31 32} The data indicated that the incidence and severity of PPE could be reduced by changing the time interval and dose intensity of PLD administration. High-dose saturation of PLD clearance may be a possible reason for such results.

The treatment of recurrent ovarian cancer with PLD in phase II clinical trials based on results after every 4 weeks at 40 mg/m² showed that the incidence of PPE was decreased compared with results after every 4 weeks at 50 mg/m², especially PPE grade 3 or higher.³³ However, there was no significant difference between median overall survival and progression-free survival. Nakayama et al used a P-score analysis to retrospectively evaluate the risk−benefit balance between PLD 40 mg/m² and 50 mg/m² every 4 weeks based on real-world data from Japan.³⁴ The data showed that the incidence and severity of PPE and stomatitis were significantly reduced by PLD40 compared with the median survival of PLD50 and PLD40 at 383 and 350 days, respectively. Based on the data above, many scholars believe that there is sufficient clinical evidence to support the use of 40 mg/m² PLD every 4 weeks for the treatment of recurrent ovarian cancer. Currently, 40 mg/m² PLD is recommended by experts in Europe and the USA and by the latest guidelines for ovarian cancer treatment in Japan.

Concomitant drugs affecting skin toxicity of PLD

Many drugs have been found to interfere with PLD clearance and its toxic effects, especially skin toxicity (table 1). Of note, platinum compounds are a class of drugs that uniquely interact with PLD. Based on the plasma concentration data, cisplatin can accelerate the clearance of PLD in the human body.^{35 36} Similar interactions may explain why PLD combined with carboplatin for ovarian cancer is well tolerated and has a good therapeutic effect.³⁷ Platinum compounds stimulate the MPS, which stimulates the immune response and accelerates the clearance of PLD. When carboplatin is used as a single drug or in combination with other drugs, life-threatening allergic reactions can occur.^{38 39} The combination of carboplatin-PLD prevents hypersensitivity to carboplatin because PLD causes mild damage or the inhibition of the MPS.^{27 40} By contrast, the combination of PLD with paclitaxel has been shown to retard PLD clearance and aggravate mucocutaneous toxicities.⁴¹

Table 1.

Pharmacokinetic drug interference on PLD clearance and/or effect on skin toxicity^*

Concomitant drug	Effect on PLD clearance	Effect on skin toxicity
Paclitaxel Docetaxel Gemcitabin+paclitaxel Valspotar Cisplatin Amifostine Trabectedin Bortezomib Ifosfamide Trastuzumab+docetaxel	Retardation Retardation Retardation Retardation Acceleration Acceleration No change No change Not tested Not tested	Aggravation Aggravation Not evaluable No change Decreased Decreased No change No change No change Aggravated

*Adapted from Gabizon et al ⁷ and references therein.

PLD, pegylated liposomal doxorubicin.

Pathogenesis of PPE

The pathogenesis of PPE has not been well established. Martschick et al used a laser scanning microscope to detect the fluorescence intensity of PLD and its metabolites in and on the skin surface of patients.⁴² The results showed that the fluorescence signal could be detected first in the skin surface and the superficial layer around the sweat duct and its openings, and later in the deep layer of stratum corneum; researchers inferred that these substances were secreted in the skin surface through sweat and then percolated and absorbed into the stratum corneum. It has also been suggested that the thick cuticle was an additional factor in PPE development because it represented a large reservoir of penetrating material. Some studies have shown that there are also high-density sweat glands in the forehead, but the stratum corneum is thin, and the detection rate of PLD and its metabolites is low. Conversely, the stratum corneum is abundant in the hand, foot, elbow and other parts, which is conducive to the accumulation of PLD and is prone to PPE. In non-clinical studies, Yokomichi et al showed that extravasation of DOX of PLD interacted with Cu(II) ions in the skin, causing reactive oxygen species and inducing apoptosis.⁴³ The Cu(II) ions rich in skin tissues interacted with DOX to activate reactive oxygen species (ROS). ROS interfered with surrounding tissues and induced keratinocyte-specific apoptosis. Keratinocytes expressed the thermoreceptor TRPM2 and stimulated the release of ROS releasing chemokines (interleukin (IL)-8, GRO, and so on), thus inducing targeted chemotaxis of neutrophils and other blood cells. Apoptosis of these cells released IL-1b, IL-1a and IL-6, leading to an inflammatory state.

Preventive measures and treatment of PPE

Treatment of PPE lacks the effectiveness of large controlled trials, most of which focus on reducing the dose and changing the interval. For severe PPE during PLD treatment, the European Society for Medical Oncology (EMSO) recommends that severe grade 3–4 PPE should be developed, treatment should be postponed for 2 weeks or until the PPE is reduced to grade 0–1, and the dose should be reduced by 25%. If the PPE does not improve after 2 weeks, PLD therapy should be discontinued.

Some non-pharmacologic treatments have been used for PPE prophylaxis, such as avoiding excessive pressure or friction on the skin and preventing dilation of blood vessels (such as a hot bath or exposure to the sun). Many retrospective studies have shown that using ice packs around the wrists and ankles is a simple and well-tolerated method of prevention.^{44 45} This may be because cooling can lead to vasoconstriction, reducing circulation of the drug in the distal extremities, which, in turn, leads to less drug extravasation into surrounding tissues and less skin toxicity. However, regional cooling is not feasible for many areas where PPE occurs.

Blaha et al used plasma filtration (PF) to study the effect of PLD clearance in vitro to determine whether PLD could be discontinued before distribution in organs other than tumour tissues.⁴⁶ The data showed that the DOX dose was eliminated by 45% (35–56%) within 44 (46) hours, PF in vitro was eliminated by 35% (22–45%) within 2.5–3.5 hours, and DOX spontaneous release was less than 8% of the total release. PPE (grade 3) was found in one of nine patients. It should be noted that this study indicated that PF could accelerate the clearance of PLD in vivo and improve the patient’s tolerance, but the tumour treatment outcome was not evaluated.

Effective drug interventions are an active area of research. Preclinical evidence supports the role of pyridoxine in preventing PLD-associated PPE. In a controlled randomised study of non-Hodgkin’s lymphoma in dogs treated with oral pyridoxine or placebo, the incidence of severe PPE and a reduced dose of PLD in those dogs treated with oral pyridoxine was significantly reduced (p=0.032).⁴⁷ However, a double-blind randomised trial comparing pyridoxine with placebo to prevent PLD-related PPE in women with gynecologic tumours showed that pyridoxine did not affect the development of PLD-related PPE.⁴⁸ Because pyridoxine is a relatively non-toxic and inexpensive treatment, some hospitals and doctors in Europe and Asia give patients 150–200 mg of pyridoxine daily for PLD-associated PPE prevention.

In addition, most reports have focused on the local use of antioxidants and free radical ointment, antiperspirant (hydroxy aluminium chloride), and dimethyl sulfoxide for the prevention and treatment of the PPE. There have also been reports of the use of amifostine and celecoxib for the prevention and treatment of PLD-associated PPE. However, these reports all require prospective randomised controlled studies to further understand and identify PPE management.

Conclusions

Because of its special liposomal formulation, PLD has a radically different pharmacokinetic profile and clinical aspects from free DOX, including a prolonged blood circulation time, small volume of distribution, better clinical effects, and toxic reactions. PPE is the distinctive dermal toxicity of PLD. To date, the mechanism of PPE induced by PLD is still unclear, and no complete preventive medication has been established. Regional cooling and plasma filtration had been used for PPE prophylaxis. Pyridoxine is widely used for the prevention and treatment of PPE. Altering the schedules and doses of PLD or combining it with other chemotherapy can optimise clinical efficacy and minimise the occurrence of drug-related toxicity. Further research and prospective randomised studies are needed to understand the management options in PLD-related PPE.

Data availability statement

Data are available in a public, open access repository.