Most anticancer drugs are characterized by a steep dose-response relationship and narrow therapeu... more Most anticancer drugs are characterized by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies for many tumour types, analytical difficulties with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials, and "Day1=Day21" administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in pediatric oncology represents an important challenge. Established TDM includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilize tools such as population PK/PD models and comparative randomized trials of classic dosing vs pharmacokineticallyguided adaptive dosing.There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.
Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples... more Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
T HE USE of drugs in common practice may substantially differ from guidelines issued from clinica... more T HE USE of drugs in common practice may substantially differ from guidelines issued from clinical trials. The reasons why usual doses prescribed in routine settings are actually either lower or higher than those recommended rely on different evidences. Specific characteristics of patients-in terms of age, co-morbidity, or concomitant absorption of other drugs-differ from those included in clinical trials; in addition, each individual presents his or her own specific variations in drug kinetics. Concerning the specific usage of FK 506 in transplantation, starting doses are recommended, although its pharmacokinetic properties can vary widely between individuals like for many other drugs. Dose regimens are consequently adjusted according to whole blood through drug concentration. 1 However, nothing compares to the daily experience of a physician with his or her patient. To assess the ordinary run of FK 506 usage in transplantation, an observatory study has been conducted in six centers in Paris, France.
... Short Report. Muscle involvement in human immunodeficiency virus-infected patients is associa... more ... Short Report. Muscle involvement in human immunodeficiency virus-infected patients is associated with marked selenium deficiency. Patrick Chariot MD 1,* ,; Marie-Laure Dubreuil-Lemaire MD 2 ,; Jiang Yan Zhou PhD 1 ,; Bouchra Lamia MSc 3 ,; Laurence Dume Pharm D 1 ,; ...
An original dosage form for oral delivery based on the encapsulation of both, lipophilic and hydr... more An original dosage form for oral delivery based on the encapsulation of both, lipophilic and hydrophilic drugs, in poly(e-caprolactone) (PCL) microparticles prepared either by the oil-in-water (o / w) or the water-in-oil-in-water (w / o / w) solvent evaporation method was developed. Microparticles were characterized in terms of morphology, size, encapsulation efficiency and drug release. The physical state of the drugs and the polymer was determined by scanning electron microscopy (SEM), X-ray powder diffractometry, and differential scanning calorimetry (DSC). Nifedipine (calcium antagonist) and propranolol HCl (b-blocker), used for the treatment of hypertension, were chosen as lipophilic and hydrophilic drugs. The microparticles were spherical with diameters in the range of 191-351 mm by the o / w-method, and in the range of 302-477 mm by the w / o / w-method. The encapsulation efficiency (EE) was 91% for nifedipine and 37% for propranolol HCl with the o / w-method, and 83% for nifedipine and 57% for propranolol HCl with the w / o / w-method. DSC and X-ray diffraction studies showed that PCL maintained its semi-crystalline structure, while the drugs were either dispersed or dissolved in the polymer. In vitro release studies revealed a controlled release of nifedipine and propranolol HCl from microparticles prepared by the o / w-method; a burst release of propranolol HCl was observed from microparticles prepared by the w / o / w-method. In conclusion, microparticles containing both a hydrophilic and a lipophilic drug were successfully prepared.
Dnrand R., Paul M., RivoIlet D., Houin R., Astier A. & Deniau M. 1997. Activity of pentamidineloa... more Dnrand R., Paul M., RivoIlet D., Houin R., Astier A. & Deniau M. 1997. Activity of pentamidineloaded methacrylate nanoparticles against Leishmonia infanturn in a mouse model. Internarional
4-Methylpyrazole (4 MP) is a strong inhibitor of alcohol dehydrogenase. Its use in acute ethylene... more 4-Methylpyrazole (4 MP) is a strong inhibitor of alcohol dehydrogenase. Its use in acute ethylene glycol (EG) or methanol intoxication has been suggested in experimental studies about its efficacy and safety. We report three cases of accidental intoxication with ethylene glycol in man treated orally with 20 mg/kg/day of 4 MP. The treatment was maintained until plasma EG concentrations became unmeasurable. The patients were admitted early during the course of the poisoning. Their neurological status was good. A slight metabolic acidosis observed in two cases was easily corrected and did not recur. Renal function remained normal in all cases. No patient underwent hemodialysis. On admission plasma EG concentrations were 24.2 mmol/l, 13 mmol/l and 9.7 mmol/l respectively. Plasma EG half-lives were 14.5, 11.5 and 14.75 hours respectively. Plasma oxalate concentrations and the rate of urine oxalate elimination, determined in two patients, were high on admission but quickly returned to normal. Concerning possible side effects of 4 MP, a skin rash was observed in one patient and a possible eosinophilia in the others. These three cases suggest that 4 MP may decrease the metabolic consequences of EG poisoning in man and may be of therapeutic value when administered early during the course of the intoxication before coma, seizures and organic renal failure have occurred.
Background. Myocardial preservation for heart transplantation relies on hyperkalemic cardiac arre... more Background. Myocardial preservation for heart transplantation relies on hyperkalemic cardiac arrest and hypothermic storage. Our study investigated whether pretreatment with a potassium-channel opener (cromakalim) before prolonged storage in an extracellular fluid improves left ventricular recovery.
Current cyclosporin (CsA) and tacrolimus (FK506) monitoring methods are based on blood concentrat... more Current cyclosporin (CsA) and tacrolimus (FK506) monitoring methods are based on blood concentrations determination, but the optimal sampling times are not clearly defined. An alternative pharmacodynamic approach has recently been introduced, based on assaying lymphocytes activity of calcineurin (PP2B), a phosphatase that is partially inhibited by CsA and FK506. However, the princeps method uses large amounts of radioactive ½ 32 Psubstrate, raising a number of safety issues. Here we describe an alternative method for PP2B activity determination, based on HPLC coupled with spectrophotometric detection. A 19-amino-acid peptide is phosphorylated by a protein kinase, and further dephosphorylated by lymphocyte PP2B in the presence of okadaic acid. The two peptides are separated by using reverse-phase chromatography with a detection wavelength of 205 nm. After lymphocyte isolation by density-gradient centrifugation, PP2B activity is derived from the dephosphorylated peptide concentration measured during the first 6 min of the enzymatic reaction. This technique gives reproducible results and good analytical sensitivity with 10 6 lymphocytes. With an average isolation rate of 59.6%, only 7 ml of blood is required, making the method suitable for lymphopenic patients. Moreover, PP2B activity is stable in blood samples kept for 24 h at room temperature and in isolated lymphocytes stored for 48 h at )20°C. We validated the method by comparing median PP2B activity in 10 healthy volunteers ð285:0 AE 46:5 pmol/min/ 10 6 lymphocytesÞ and in 10 liver transplant patients ð147:8 AE 71:0 pmol/min/10 6 lymphocytesÞ (p < 0:001). The relation between calcineurin activity and tacrolimus blood concentrations was also studied.
... Frédéric J. Baud, MD, Martine Galliot, Pharm.D., Alain Astier, Ph.D., Dang Vu Bien, Pharm.D.,... more ... Frédéric J. Baud, MD, Martine Galliot, Pharm.D., Alain Astier, Ph.D., Dang Vu Bien, Pharm.D., Robert Garnier, MD, Joseph Likforman, Pharm.D ... We are indebted to T. Meredith, MD, and D. Jacobsen, MD, for helpful criticism in reviewing the manuscript, and to J. Johnston, MD, for ...
Most anticancer drugs are characterized by a steep dose-response relationship and narrow therapeu... more Most anticancer drugs are characterized by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies for many tumour types, analytical difficulties with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials, and "Day1=Day21" administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in pediatric oncology represents an important challenge. Established TDM includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilize tools such as population PK/PD models and comparative randomized trials of classic dosing vs pharmacokineticallyguided adaptive dosing.There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.
Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples... more Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.
T HE USE of drugs in common practice may substantially differ from guidelines issued from clinica... more T HE USE of drugs in common practice may substantially differ from guidelines issued from clinical trials. The reasons why usual doses prescribed in routine settings are actually either lower or higher than those recommended rely on different evidences. Specific characteristics of patients-in terms of age, co-morbidity, or concomitant absorption of other drugs-differ from those included in clinical trials; in addition, each individual presents his or her own specific variations in drug kinetics. Concerning the specific usage of FK 506 in transplantation, starting doses are recommended, although its pharmacokinetic properties can vary widely between individuals like for many other drugs. Dose regimens are consequently adjusted according to whole blood through drug concentration. 1 However, nothing compares to the daily experience of a physician with his or her patient. To assess the ordinary run of FK 506 usage in transplantation, an observatory study has been conducted in six centers in Paris, France.
... Short Report. Muscle involvement in human immunodeficiency virus-infected patients is associa... more ... Short Report. Muscle involvement in human immunodeficiency virus-infected patients is associated with marked selenium deficiency. Patrick Chariot MD 1,* ,; Marie-Laure Dubreuil-Lemaire MD 2 ,; Jiang Yan Zhou PhD 1 ,; Bouchra Lamia MSc 3 ,; Laurence Dume Pharm D 1 ,; ...
An original dosage form for oral delivery based on the encapsulation of both, lipophilic and hydr... more An original dosage form for oral delivery based on the encapsulation of both, lipophilic and hydrophilic drugs, in poly(e-caprolactone) (PCL) microparticles prepared either by the oil-in-water (o / w) or the water-in-oil-in-water (w / o / w) solvent evaporation method was developed. Microparticles were characterized in terms of morphology, size, encapsulation efficiency and drug release. The physical state of the drugs and the polymer was determined by scanning electron microscopy (SEM), X-ray powder diffractometry, and differential scanning calorimetry (DSC). Nifedipine (calcium antagonist) and propranolol HCl (b-blocker), used for the treatment of hypertension, were chosen as lipophilic and hydrophilic drugs. The microparticles were spherical with diameters in the range of 191-351 mm by the o / w-method, and in the range of 302-477 mm by the w / o / w-method. The encapsulation efficiency (EE) was 91% for nifedipine and 37% for propranolol HCl with the o / w-method, and 83% for nifedipine and 57% for propranolol HCl with the w / o / w-method. DSC and X-ray diffraction studies showed that PCL maintained its semi-crystalline structure, while the drugs were either dispersed or dissolved in the polymer. In vitro release studies revealed a controlled release of nifedipine and propranolol HCl from microparticles prepared by the o / w-method; a burst release of propranolol HCl was observed from microparticles prepared by the w / o / w-method. In conclusion, microparticles containing both a hydrophilic and a lipophilic drug were successfully prepared.
Dnrand R., Paul M., RivoIlet D., Houin R., Astier A. & Deniau M. 1997. Activity of pentamidineloa... more Dnrand R., Paul M., RivoIlet D., Houin R., Astier A. & Deniau M. 1997. Activity of pentamidineloaded methacrylate nanoparticles against Leishmonia infanturn in a mouse model. Internarional
4-Methylpyrazole (4 MP) is a strong inhibitor of alcohol dehydrogenase. Its use in acute ethylene... more 4-Methylpyrazole (4 MP) is a strong inhibitor of alcohol dehydrogenase. Its use in acute ethylene glycol (EG) or methanol intoxication has been suggested in experimental studies about its efficacy and safety. We report three cases of accidental intoxication with ethylene glycol in man treated orally with 20 mg/kg/day of 4 MP. The treatment was maintained until plasma EG concentrations became unmeasurable. The patients were admitted early during the course of the poisoning. Their neurological status was good. A slight metabolic acidosis observed in two cases was easily corrected and did not recur. Renal function remained normal in all cases. No patient underwent hemodialysis. On admission plasma EG concentrations were 24.2 mmol/l, 13 mmol/l and 9.7 mmol/l respectively. Plasma EG half-lives were 14.5, 11.5 and 14.75 hours respectively. Plasma oxalate concentrations and the rate of urine oxalate elimination, determined in two patients, were high on admission but quickly returned to normal. Concerning possible side effects of 4 MP, a skin rash was observed in one patient and a possible eosinophilia in the others. These three cases suggest that 4 MP may decrease the metabolic consequences of EG poisoning in man and may be of therapeutic value when administered early during the course of the intoxication before coma, seizures and organic renal failure have occurred.
Background. Myocardial preservation for heart transplantation relies on hyperkalemic cardiac arre... more Background. Myocardial preservation for heart transplantation relies on hyperkalemic cardiac arrest and hypothermic storage. Our study investigated whether pretreatment with a potassium-channel opener (cromakalim) before prolonged storage in an extracellular fluid improves left ventricular recovery.
Current cyclosporin (CsA) and tacrolimus (FK506) monitoring methods are based on blood concentrat... more Current cyclosporin (CsA) and tacrolimus (FK506) monitoring methods are based on blood concentrations determination, but the optimal sampling times are not clearly defined. An alternative pharmacodynamic approach has recently been introduced, based on assaying lymphocytes activity of calcineurin (PP2B), a phosphatase that is partially inhibited by CsA and FK506. However, the princeps method uses large amounts of radioactive ½ 32 Psubstrate, raising a number of safety issues. Here we describe an alternative method for PP2B activity determination, based on HPLC coupled with spectrophotometric detection. A 19-amino-acid peptide is phosphorylated by a protein kinase, and further dephosphorylated by lymphocyte PP2B in the presence of okadaic acid. The two peptides are separated by using reverse-phase chromatography with a detection wavelength of 205 nm. After lymphocyte isolation by density-gradient centrifugation, PP2B activity is derived from the dephosphorylated peptide concentration measured during the first 6 min of the enzymatic reaction. This technique gives reproducible results and good analytical sensitivity with 10 6 lymphocytes. With an average isolation rate of 59.6%, only 7 ml of blood is required, making the method suitable for lymphopenic patients. Moreover, PP2B activity is stable in blood samples kept for 24 h at room temperature and in isolated lymphocytes stored for 48 h at )20°C. We validated the method by comparing median PP2B activity in 10 healthy volunteers ð285:0 AE 46:5 pmol/min/ 10 6 lymphocytesÞ and in 10 liver transplant patients ð147:8 AE 71:0 pmol/min/10 6 lymphocytesÞ (p < 0:001). The relation between calcineurin activity and tacrolimus blood concentrations was also studied.
... Frédéric J. Baud, MD, Martine Galliot, Pharm.D., Alain Astier, Ph.D., Dang Vu Bien, Pharm.D.,... more ... Frédéric J. Baud, MD, Martine Galliot, Pharm.D., Alain Astier, Ph.D., Dang Vu Bien, Pharm.D., Robert Garnier, MD, Joseph Likforman, Pharm.D ... We are indebted to T. Meredith, MD, and D. Jacobsen, MD, for helpful criticism in reviewing the manuscript, and to J. Johnston, MD, for ...
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