The thalidomide disaster, lessons from the past.

It is close to 60 years since thalidomide was created by the German company, Chemie-Grünenthal, and launched as "Contergan." This was soon to be followed in England by the launch of "Distaval." Of all the drugs developed in the intervening years, thalidomide has undoubtedly had the greatest influence on shaping the Pharmaceutical Industry as we know it today.Strong marketing pressure in an Industry hungry for new medicines brought an inadequately tested drug to the market, targeted outsourcing quickly expanded the client base and finally market forces prevented timely withdrawal, even when evidence was emerging of disastrous side-effects. The full story of thalidomide was told by the Sunday Times in "Suffer The Children" (Kingsley et al., Suffer the children: the story of thalidomide, the insight team of the Sunday times (UK), 1979).Many preventative measures have been taken in the intervening years in light of the lessons learned with thalidomide. However, many of the pressures that led to the thalidomide disaster exist today with record high management and shareholder pressures to achieve success, parallel worldwide marketing, increased numbers of targeted outsourcing by small companies forming alliances with "Big Pharma" and, according to some commentators, a breakdown in the system of checks and balances that have existed in the regulatory authorities in the intervening years.Using thalidomide as a point of reference, this chapter looks at drug development and testing, regulatory authorities and guidelines, outsourcing and in-licensing, pharmacovigilance, and factors that influence withdrawal of a drug from the market.

The penumbra of thalidomide, the litigation culture and the licensing of pharmaceuticals.

Fifty years ago several thousand children were born with severe limb defects after their mothers had been given thalidomide in pregnancy. This tragedy caused procedures for licensing new medicines to become much stricter. Where, nevertheless, significant side effects were found it became common to sue for damages. These consequences have caused possibly an even greater disaster damaging many more people and threatening ruin to health services everywhere. The huge increase in both time and cost in bringing medicines to market is increasing their price to unsupportable levels; and only wealthy companies are now able to do so. This requires reform as does litigation for 'statistical' harmful effects.

Talidomida y análogos de talidomida / Thalidomide and analogous

La talidomida se introdujo en la década del 50 como droga hipnótica, sedante y antiemética, especialmente indicada en mujeres gestantes durante el primer trimestre del embarazo. Se asociaron al uso del fármaco graves anormalidades congénitas y polineuropatías, por lo que se la retiró del mercadoen los años 60. Posteriormente se comprobaron propiedades inmunomoduladoras en pacientes con eritema nudoso lepromatoso, así como también efectos antiinflamatorios como lupus eritematoso discoide, enfermedad de Behcet, úlceras aftosas en pacientes con SIDA, enfermedad crónica injerto contra huésped, mieloma múltiple y neoplasia de órganos sólidos. Actualmente, con el desarrollo de nuevos fármacos análogos de la talidomida, que conservan sus propiedades terapéuticas sin presentar teratogenicidad, su aplicación futura es más promisoria (AU)

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...

The combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) is feasible and can be an option for relapsed/refractory multiple myeloma.

INTRODUCTION: Thalidomide has recently proven to be a useful drug for treatment of refractory and relapsed multiple myeloma patients, up to 35% of whom achieve remission. However, little is known about the potential additive or synergistic effect upon its association with other drugs with proven efficacy in MM. MATERIAL AND METHODS: The present pilot study was designed to evaluate the toxicity and response rate of the association of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex) in 22 refractory or relapsed MM patients. The protocol scheduled the administration of thalidomide at escalating doses (200 to 800 mg/day), daily oral cyclophosphamide (CTX) (50 mg/day) and pulsed dexamethasone (40 mg/day, four days every three weeks). RESULTS: Adverse effects were moderate (grade or=2 were noted. Other side effects included grade 50% M-component reduction (two of them with a complete remission). Only two responders have already progressed, with a projected event free survival of 51% at 12 months. Seven patients have died due to disease progression (n=5), sudden death (n=1) and infection (n=1). CONCLUSION: This study shows that ThaCyDex is a feasible and promising therapeutic approach for patients with relapsed/refractory MM.