Population Pharmacokinetic Model to Assess the Impact of Disease State on Thalidomide Pharmacokinetics.

A population pharmacokinetic (PPK) model to describe the pharmacokinetics of thalidomide in different patient populations was developed using data pooled from healthy subjects and patients with Hansen's disease, human immunodeficiency virus (HIV), and multiple myeloma (MM). The analysis data set had a total of 164 evaluable subjects who received various doses (50 to 400 mg) of oral thalidomide in single- and/or multiple-dose regimens. The plasma thalidomide concentrations were adequately described by a linear 1-compartment PPK model with first-order absorption and first-order elimination. Inclusion of MM as a covariate on apparent clearance (CL/F) accounted for 4.4% of the interindividual variability (IIV) of CL/F. Body weight as a covariate on CL/F and apparent volume of distribution (V/F) also improved model fitting slightly, accounting for 7.2% and 20% of IIV, respectively. Although inclusion of body weight and MM as covariates of CL/F and body weight on V/F improved the goodness of fit of the model in a statistically significant manner, the impact of this difference in CL/F is not considered clinically relevant. Other factors such as age, sex, race, creatinine clearance, and alanine transaminase had no effect on thalidomide pharmacokinetics. MM, HIV, and Hansen's disease have no clinically relevant effect on thalidomide disposition relative to healthy volunteers.

Systematic evaluation of the impact of solid-state polymorphism on the bioavailability of thalidomide.

Thalidomide (TLD) is used to treat erythema nodosum leprosum (ENL), multiple myeloma, aphthous ulceration and wasting syndrome in HIV patients. The API can be found in two crystalline habits known as α-TLD and ß-TLD. The saturation solubility (Cs) and the dissolution profiles under non-sink and sink conditions of both polymorphs were assessed. In addition, mini-capsules containing α-TLD or ß-TLD without excipients were orally given (10 mg/kg) to Wistar rats. An intravenous (i.v.) dose was also administrated (5 mg/kg). The Cs values for α-TLD and ß-TLD were not significantly different (α = 56.2 ±â€¯0.5 µg·mL-1; ß = 55.2 ±â€¯0.2 µg·mL-1). However, the dissolution profile of α-TLD presented the fastest rate and the largest extension of drug dissolution than that from ß-TLD (80% in 4 h versus 55% in 4 h). The α-TLD provided a more favorable pharmacokinetic than the ß-TLD (maximum plasma concentration - Cmax: 5.4 ±â€¯0.90 µg·mL-1versus 2.6 ±â€¯0.2 µg·mL-1; area under the curve of the concentration-time profile from time zero to infinity - AUC0-∞: 44.3 ±â€¯8.8 µg·h·mL-1versus 33.9 ±â€¯4.7 µg·h·mL-1; absolute bioavailability - F: 92.2 ±â€¯18.5% versus 70.5 ±â€¯9.9%, respectively). Drug suppliers and pharmaceutical companies should strictly control the technological processes involved in the TLD API synthesis as well as in the production of the pharmaceutical dosage form in order to guarantee the inter-batch homogeneity and therefore, product compliance.

Clinical evidence of pharmacokinetic changes in thalidomide therapy.

The teratogenic effects of thalidomide have been studied for more than 50 years. However, there have been few studies of the pharmacokinetic changes occurring during thalidomide therapy. Thalidomide was originally developed as a sedative. However, thalidomide induces multiple birth defects when used in pregnant women. Thalidomide is now used in the treatment of multiple myeloma (MM) and erythema nodosum leprosum (ENL) in Japan. Rational use of thalidomide is problematic due to a lack of basic research regarding its mechanism of action and serum concentration/effect relationships. There are a number of hypotheses for pharmacokinetic changes in thalidomide therapy. Genetic factors including single nucleotide polymorphisms (SNPs) that change cytochrome P450 (CYP) activity and epigenetic regulation that modifies CYP expression levels may contribute to the changes in pharmacokinetics and adverse drug reactions (ADRs) of thalidomide. Environmental factors include the pharmacological context of drug-drug interactions and the physiological context of liver diseases. Liver and kidney diseases do not play important roles in pharmacokinetic changes or ADRs in thalidomide therapy. To date, most research has focused on teratogenic activity, while the impact of polymorphisms in genes encoding drug metabolic enzymes and drug-drug interactions could mediate ADRs. Here, we discuss clinical evidence of pharmacokinetic changes in thalidomide therapy.

Teratogenic effects of thalidomide: molecular mechanisms.

Fifty years ago, prescription of the sedative thalidomide caused a worldwide epidemic of multiple birth defects. The drug is now used in the treatment of leprosy and multiple myeloma. However, its use is limited due to its potent teratogenic activity. The mechanism by which thalidomide causes limb malformations and other developmental defects is a long-standing question. Multiple hypotheses exist to explain the molecular mechanism of thalidomide action. Among them, theories involving oxidative stress and anti-angiogenesis have been widely supported. Nevertheless, until recently, the direct target of thalidomide remained elusive. We identified a thalidomide-binding protein, cereblon (CRBN), as a primary target for thalidomide teratogenicity. Our data suggest that thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting its ubiquitin ligase activity. In this review, we summarize the biology of thalidomide, focusing on the molecular mechanisms of its teratogenic effects. In addition, we discuss the questions still to be addressed.

Thalidomide in multiple myeloma--clinical trials and aspects of drug metabolism and toxicity.

BACKGROUND: After the tragic events in the early 1960s, thalidomide has re-emerged as therapeutic for multiple myeloma (MM). It was first approved for the treatment of erythema nodosum leprosum, and is now under evaluation for hematologic and non-hematologic disorders. Its complex mechanism of action is not fully understood; however extensive preclinical studies in MM have revealed its antiangiogenic and immunomodulatory properties. OBJECTIVE: In this review, we focus on the importance and toxicity of thalidomide in today's clinical use. METHODS: Key preclinical and clinical trials available as well as data on the pharmacokinetics and pharmacodynamics of thalidomide in humans are summarized. CONCLUSIONS: Thalidomide is widely used as first-line treatment and in relapsed/refractory MM. The most common side effects are fatigue, constipation and peripheral neuropathy, and careful monitoring is required to avoid fetal exposure.

Thalidomide suppressed interleukin-6 but not tumor necrosis factor-alpha in volunteers with experimental endotoxemia.

An early rationale for using thalidomide to treat erythema nodosum leprosum had been based on some reports that it suppresses tumor necrosis factor-alpha (TNF-alpha). However, in vivo and in vitro studies have yielded variable results, having shown that thalidomide can either enhance or suppress TNF-alpha. Since the course of circulating cytokines like TNF-alpha after infusion of endotoxin into volunteers is reproducible and characteristic, we investigated the effect of thalidomide on endotoxin-induced synthesis of TNF-alpha, interleukin (IL)-6, and IL-8. The cytokine response from 18 placebo-treated subjects who had undergone the endotoxin challenge were pooled with a placebo-treated subject from the current study and were compared with 4 subjects who received thalidomide (100 mg) every 6 h for 5 doses before endotoxin challenge. Thirty minutes after the last dose of thalidomide or placebo, volunteers were infused with 4-ng/kg endotoxin. Plasma was collected and assayed for cytokines by enzyme-linked immunosorbent assay. Endotoxin evoked the synthesis of the cytokines in all volunteers. The peak response for TNF-alpha was 1.5 h, 2.5 h for IL-8, and 3.0 h for IL-6. Thalidomide did not significantly delay the release of cytokines into the circulating blood. At the peak response, thalidomide reduced the concentration of the cytokines in the plasma. Using the area under the dose response curve (AUC(0 to 24) h), thalidomide reduced the AUC for IL-6 by 56%, for IL-8 by 30%, and TNF-alpha by 32%. In this model, thalidomide did not suppress TNF-alpha or IL-8, but it did suppress IL-6 at 4-h postinfusion with lipopolysaccharide (P=0.004), at 6 h (P=0.014), at 12 h (P=0.001), and at 16 h (P=0.012).

[New pharmacological availability of thalidomide based on experience in patients with multiple myeloma].

Thalidomide was developed in the 1950s as a sedative having only a low toxicity. However, McBride and Lenz reported in 1961 a close correlation between oral administration of thalidomide by pregnant women and a particular deformity (phocomelia) of their babies. In the 1990s, the biological activities of thalidomide were determined to include the control of tumor necrosis factor-alpha production and inhibition of angiogenesis. In 1994, Folkman et al. reported that thalidomide exhibited a strong inhibition of angiogenesis in their experiments with rabbits and that this effect had a significant relationship to phocomelia. They suggested a utility of thalidomide as a therapeutic agent for diseases that involve angiogenesis, particularly tumorous diseases. Furthermore, in 1994, Vacca et al. reported that the bone marrow of multiple myeloma (MM) patients was rich in blood vessels and that there is a causal relationship between the activity of MM and marrow angiogenesis. According to these data, thalidomide was tested in many countries as a new therapeutic agent for MM. In this review, new pharmacological availability of thalidomide is described on the basis of our experiences.

Talidomida: una visión nueva de un tóxico antiguo / Thalidomide: a new view of an old toxic

Desde que a principios de los años 60 la talidomida fuera retirada del mercadodebido a su acción teratogénica, este fármaco ha sido ampliamente estudiado,encontrándose en él propiedades terapéuticas que han despertado nuevamente elinterés por esta molécula. Recientemente, la FDA ha aprobado su empleo en eltratamiento de ENL (Erythema Nodosum Leprosum), una manifestación aguda dela lepra. Además, actualmente se encuentra en ensayos clínicos (fase II/III) enmieloma múltiple, cáncer de mama, próstata, riñón y pulmón, mostrando buenosresultados. En este artículo se ofrece una visión general de las propiedades de latalidomida, haciendo especial hincapié en su acción inhibitoria de la angiogénesis,que podría ser responsable, al menos en parte, de su actividad antineoplásica yteratogénica

Since the early 60s, when thalidomide was withdrawn from markets, this drug ;;has been widely studied due to its teratogenic activity. The finding of new therapeutic properties has raised a new interest in this molecule, and recently the FDA ;;has approved its use in the treatment of ENL (Erythema Nodosum Leprosum), an ;;acute manifestationof leprae. Besides, thalidomide is nowadays going through clinical ;;assays (PhaseII/III) in multiple myeloma, breast, prostate, kidney and lung ;;tumours, showing good results. This article offers an overview of thalidomide ;;properties focusing on its inhibition of angiogenesis, which would be responsible, ;;at least partially, of its antineoplastic and teratogenic activity

Clinical pharmacokinetics of thalidomide.

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions is being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200 mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (C(max)) of 1-2 mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUC( infinity )) of 18 mg. h/L, apparent elimination half-life of 6 hours and apparent systemic clearance of 10 L/h. Thalidomide pharmacokinetics are best described by a one-compartment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacokinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than its absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state C(max) (C(ss)(max)) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accumulation, with C(ss)(max) of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400 mg. Because of the low solubility of thalidomide, C(max) is less than proportional to dose, and t(max) is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokinetics are not expected to change in patients with impaired liver or kidney function.

Clinical pharmacokinetics of thalidomide

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions in being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (Cmax) of 1-2mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUCoo) of 18mg - h/L, apparent elimination half-life of 6 hours and apparent systemic clearence of 10 L/H. Thalidomide pharmacokinetics are best described by a one-comportment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacolinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than in absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state Cmax (Cssmax) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accululation, with Css of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400mg. Because of the low solubility of thalidomide Cmax is less than proportional to dose, and tmax is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokonetics are not expected to change in patients with impaired liver...

Thalidomide in the treatment of leprosy.

Leprosy is a chronic infection of the skin and nerves caused by Mycobacterium leprae. Erythema nodosum leprosum (ENL) is a reactive state in lepromatous leprosy. Thalidomide has been used to treat ENL since the 1960s. One of its mechanisms of action is anti-inflammatory through selective inhibition of the pro-inflammatory cytokine TNF-alpha produced by monocytes.

Thalidomide in the treatment of leprosy

Leprosy is a chronic infection of the skin and nerves caused by Mycobacterium leprae. Erythema nodosum leprosum (ENL) is a reactive state in lepromatous leprosy. Thalidomide has been used to treat ENL since the 1960s. One of its mechanisms of action is anti-inflammatory through selective inhibition of the pro-inflammatory cytokine TNF-alpha produced by monocytes.

Thalidomide dose proportionality assessment following single doses to healthy subjects.

Thalidomide is approved in the United States for treating erythema nodosum leprosum, a complication of leprosy. The present study determined the single-dose oral pharmacokinetics and dose proportionality from 50 to 400 mg of Celgene's commercial Thalomid thalidomide formulation in an open-label, single-dose, three-way crossover study. Fifteen healthy subjects were given 50, 200, and 400 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using noncompartmental methods, and dose proportionality was assessed by linear regression of dose-normalized Cmax and AUC0-infinity. No serious or unexpected adverse events occurred. The most common adverse events were dizziness, somnolence, headache, and nausea. One patient was discontinued because of pharyngitis. There was a significant deviation from proportionality for Cmax with increases being less than proportional than changes in dose. AUC0-infinity increased proportionally with dose, suggesting that the overall amount of thalidomide absorbed, as well as its clearance, is independent of dose over the range used. V/F was found to increase with dose. This was most likely due to the terminal rate constant, which is used to calculate V/F, actually representing the absorption process rather than elimination (i.e., flip-flop phenomenon). The terminal rate constant (absorption rate constant) for the highest dose was 50% less than for the other two lower doses. The less than proportional increases in Cmax were most likely due to thalidomide's low aqueous solubility. Thalidomide shows reasonable dose proportionality with respect to AUC from 50 to 400 mg.

Thalomid (Thalidomide) capsules: a review of the first 18 months of spontaneous postmarketing adverse event surveillance, including off-label prescribing.

The sedative/hypnotic thalidomide was withdrawn from the worldwide market nearly 40 years ago, because of its teratogenic and neurotoxic effects. Thalidomide was later found to very effectively suppress erythema nodosum leprosum (ENL). The US Food and Drug Administration (FDA) has approved Thalomid (thalidomide) capsules for the acute treatment of the cutaneous manifestations of moderate to severe ENL. Thalidomide is currently under investigation for the treatment of a wide variety of diseases, including conditions thought to have an inflammatory or immune basis, malignancies and complications of infection with HIV. Interest in the potential anti-inflammatory, immunomodulatory and anti- angiogenic effects of thalidomide has resulted in off-label use of prescription thalidomide. During the first 18 months of spontaneous postmarketing adverse event surveillance for Thalomid, 1210 spontaneous postmarketing adverse event reports were received for patients treated with prescription thalidomide for all therapeutic indications, including off-label use. The most common adverse events spontaneously reported would have been expected on the basis of the current Thalomid labelling/product information. The current labelling/product information reflects what was known about the risks associated with thalidomide therapy in limited patient populations at the time of the approval of Thalomid. With the postmarketing use of thalidomide in populations other than patients with ENL, it becomes increasingly important to identify patient groups that may be particularly susceptible to specific adverse drug effects and to identify conditions under which specific adverse events may be more likely to occur. Oncology patients may represent a patient population with increased susceptibility to thalidomide-associated adverse effects, including thromboembolic events. Consideration of the spontaneous postmarketing safety surveillance data may help to identify and characterise factors associated with increased risk in this and other patient groups. Serious unexpected adverse events reported with sufficient frequency to signal previously undetected product-event associations for which there may potentially be plausible evidence to suggest a causal relationship have included seizures and Stevens-Johnson syndrome. The potential effects of thalidomide on wound healing are also being closely monitored. Premarketing human clinical trials of drug products are inherently limited in their ability to detect adverse events. Broader postmarketing experience with thalidomide in more varied patient populations and more experience in the setting of long term thalidomide use will increase our ability to detect rare adverse events and to identify signals that may need to be evaluated in more controlled settings.

Metabolism of thalidomide in human microsomes, cloned human cytochrome P-450 isozymes, and Hansen's disease patients.

Previous in vitro studies in rat microsomal preparations suggested that thalidomide is metabolized by the cytochrome P450 system (CYP). In this study, we examined the extent of thalidomide metabolism by preparations of pooled human microsomes, microsomes containing cloned human CYP isozymes (CYPIA2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4), and Hansen's disease patients. Results indicated that thalidomide was a poor substrate for CYP isozymes. Alteration of incubation buffer, pH, incubation time, and microsome and thalidomide concentrations did not increase the production of any metabolites. Thalidomide also did not inhibit metabolism of CYP-specific substrates and therefore any interactions with other drugs that are metabolized by the same enzyme system are unlikely. Hansen's patients were given a single oral dose of thalidomide (400 mg), and their blood and urine were collected at time points up to 72 hours, processed, and analyzed by tandem mass spectrometry. Although thalidomide was present in the plasma and urine, no metabolites were found in the plasma and very low amounts of the 5-OH thalidomide metabolite were present in the urine. These results suggest that thalidomide does not undergo significant metabolism by human CYP and that clinically important interactions between thalidomide and drugs that are also metabolized by this enzyme system are unlikely. The major route of thalidomide breakdown in humans and animals is through spontaneous hydrolysis with subsequent elimination in the urine.

Thalidomide: a re-look.

Thalidomide was synthesized in 1954 in erstwhile West Germany and marketed as a sedative in over 46 countries until the early 1960s. Owing to serious teratogenic effects, the drug was withdrawn from the market in 1961. A chance observation suggested the utility of thalidomide in erythema nodosum leprosum (ENL). After many controlled and uncontrolled trials were published, the World Health Organization recommended its use in ENL. The Food and Drug Administration, USA approved it for use in ENL in July 1998. Only established and well-defined studies conducted to substantiate the efficacy of thalidomide have been included in this review. Thalidomide is considered the drug of choice for the treatment of ENL, but for other conditions, it is recommended only when resistance to the currently available form of therapy is encountered. Once the anti-inflammatory, immuno-modulatory, anti-TNF-alpha and anti-angiogenic properties of thalidomide were discovered, it was also tried in AIDS and related wasting, apthous ulcers, microsporidiosis and Kaposi's sarcoma. Thalidomide has no clinical place as an immunosuppressant in solid organ transplantation. However, it has a therapeutic role in graft-verus-host-disease. Among the dermatological conditions, thalidomide has been found to be effective in systemic lupus erythematosus, discoid lupus erythematosus, actinic prurigo and prurigo nodularis. Used correctly, it is a safe and effective medicine (except for its teratogenic potential and delayed neuropathy) in a variety of disease conditions.

Thalidomide: a remarkable comeback.

The thalidomide product is a racemic mixture of the L- and D-enantiomeric forms of a synthetic glutamic acid derivative that contains a phthalimide ring and a glutarimide ring. Initially marketed as a sedative, it was withdrawan from the world market after it was found to be associated with severe birth defects. Recently, the compound has generated renewed interest because of its immunomodulatory and anti-angiogenic properties. The nature of its immunologic effects is under active investigation. It is orally bioavailable and can be administered in once daily dosing. Its primary route of metabolism is spontaneous hydrolysis. In controlled clinical trials, thalidomide has proven effective in the treatment of erythema nodosum leprosum, oral and oesophageal aphthous ulceration associated with advanced HIV infection and oral ulceration associated with Behcet's syndrome. Promising results have been obtained in preliminary studies of other immunologic and neoplastic disorders, but controlled clinical studies are still lacking for these entities. Adverse effects include teratogenicity, peripheral neuropathy and sedation. In the US, thalidomide can be prescribed only through a restricted drug distribution program.