Eur J Clin Pharmacol (2016) 72:247–248 DOI 10.1007/s00228-015-1956-2
LETTER TO THE EDITORS
Deferasirox-induced serious adverse reaction in a pediatric patient: pharmacokinetic and pharmacogenetic analysis M. Marano 1 & G. Bottaro 2 & B. Goffredo 3 & F. Stoppa 1 & M. Pisani 4 & A. M. Marinaro 5 & F. Deodato 6 & C. Dionisi-Vici 6 & E. Clementi 7,8 & F. S. Falvella 9
Received: 4 September 2015 / Accepted: 18 September 2015 / Published online: 24 September 2015 # Springer-Verlag Berlin Heidelberg 2015
Keywords Deferasirox . Adverse events . Hyperchloremic metabolic acidosis . Hyperammonemia
We report the case of a 3-year-old girl affected by major thalassemia. She was treated with Deferasirox (DFR), an oral iron chelator, at the dosage of 33 mg/kg per day since the age of 2 years. During the following months, the child underwent three admissions for fever, vomiting, metabolic acidosis, increased azotemia and dehydration. One episode
* M. Marano [email protected] 1
DEA Intensive Care Unit, IRCCS BBambino Gesù^ Children Hospital, Piazza S. Onofrio 4, Rome 00165, Italy
2
Department of Pediatrics BTor Vergata University^, Rome, Italy
3
Laboratory of Analytical Biochemistry, IRCCS BBambino Gesù^ Children Hospital, Rome, Italy
4
DEA, IRCCS BBambino Gesù^ Children Hospital, Rome, Italy
5
Department of Pediatrics, Section of Pediatrics Haematology and Oncology, University of Sassari, Sassari, Italy
6
Department of Pediatric Medicine, Division of Metabolism, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
7
Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy
8
Department of Biomedical and Clinical Sciences L. Sacco, Unit of Clinical Pharmacology, CNR Institute of Neuroscience, BLuigi Sacco^ University Hospital, University of Milano, Milan, Italy
9
Department of Biomedical and Clinical Sciences, Unit of Clinical Pharmacology, BLuigi Sacco^ University Hospital, University of Milano, Milan, Italy
was characterised by elevation of transaminases (AST 472 U/L, ALT 479 U/L). During this period, weight loss (from 15 to 12 kg) and behavioural changes were observed. After 1 month, the girl was admitted to a local hospital for vomiting, stuporous state, lockjaw, and myoclonus. The cerebral CT scan was normal. Exams showed elevated ammonia level in three determinations (741–744–536 mcg/dl), hypoglycemia (36 mg/dl), elevation of transaminases (AST 42 U/L, ALT 148 U/L) alkaline phosphatase 396 U/L, INR 1.36. DFR was discontinued. A urea cycle disorder was first suspected, protein intake was stopped, and intravenous glucose solution, arginine and sodium benzoate infusion was started. She was transferred to our PICU. On her arrival (20 h later), exams showed hyperchloremic metabolic acidosis (pH 7.19, Cl− 122 mmol/L, Lac 0.7 mmol/L, BE −17 mmol/L, HCO3− 11 mmol/L), anion gap 9 mmol/L, hypophosphoremia (1.5 mg/dl), normal ammonia and transaminases. Blood lactate, plasma amino acids and acylcarnitines were normal, while urinary organic acids analysis showed an increase of lactic, 3OH butyric, pyruvic, citric, succinic and fumaric acids. Glycosuria, proteinuria, hemoglobinuria, ketonuria and leucocyturia were present with increase of β2-microglobulin. Hemolytic uremic syndrome and sepsis were excluded. Because of the persisting metabolic acidosis and oligo-anuria, a continuous venovenous hemodialysis (CVVHD) treatment was started. The child had showed a progressive improvement and was discharged after 2 weeks. Even if DFR recommended dosage is 20–30 mg/kg per day, it has been reported that in transfused children, a good iron balance is achieved with DFR dosage ≥30 mg/kg per day [1]. Nevertheless, the European Medicines Agency has revealed an increase of adverse events (AE) with DFR dosage >30 mg/kg per day. In children, the commonest AE include vomiting, abdominal pain,
248 Table 1
Eur J Clin Pharmacol (2016) 72:247–248 Pharmacogenetic analyses performed in our case
Protein
Gene
UGT1A1
UGT1A1
Variant
Orientation strand
SNP ID
MAF
Functional effect
Case genotype
*6/c.211G>A
Forward
rs4148323
0.03
Decreased activity
GG
*28/(TA)6>(TA)7
Forward
rs8175347
0.32
Reduced expression
(TA)6TA)6
*60/-3279T>G *93/-3156G>A
Forward Forward
rs4124874 rs10929302
0.47 0.30
Reduced expression Reduced expression
TG GG
MRP2
ABCC2
c.-24C>T c.4544G>A
Forward Forward
rs717620 rs8187710
0.14 0.07
Decreased activity Impaired ATPase activity
CT GA
BCRP
ABCG2
c.421C>A
Reverse
rs2231142
0.12
Reduced protein levels
GG
Genotypes associated to a poor metabolizer or impaired transporter activity are italicized. For further and updated information on variants and population frequency please see http://www.ensembl.org/index.html or http://www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles/ MAF minor allele frequency
transaminases and blood creatinine increase, fever, nausea, diarrhea and liver damage [2]. Given the possible association of the symptomatology of our patient with DFR assumption and considering the negativity of all other examinations, it was decided to evaluate the drug plasmatic concentration and perform a pharmacogenetic analysis. DFR is metabolised by uridine diphosphate glucuronosyltransferase (UGT) and eliminated into the bile through multidrug resistance protein 2 (MRP2) and breast cancer resistance protein (BCRP) [3]. Defective UGT1A1 alleles and polymorphisms of ABCC2 and ABCG2 coding for MRP2 and BCRP proteins may eventually contribute to the development of drug-related AE [4–7]. As reported in Table 1, our patient has been found carrier of UGT1A1 and ABCC2 polymorphisms explaining a possible reduction of DFR metabolism together with a reduction of biliary elimination by MRP2. Since MRP2 transports the drug also from the cells to the tubular lumen, an impaired transporter activity leads to intracellular drug accumulation with nephrotoxicity. Our patient presented glycosuria, proteinuria, hyperchloremic metabolic acidosis, hypophosphoremia and increased β2-microglobulin, all features compatible with renal proximal tubular injury [8, 9]. In our patient, hyperammonemia due to inborn errors of metabolism was ruled out. We assume that a reduced metabolism genetically determined might have caused an accumulation of DFR, confirmed by increased plasmatic levels (186 mg/ml, normal range 0.16–40). This could have caused a liver and kidney drug toxicity, also considering the exclusion of any other possible cause and the application of the Naranjo algorithm (score 10) [10]. This case highlights a potential risk of toxicity in subjects requiring iron-chelating therapy stressing the need for a close and careful monitoring.
References 1.
2.
3.
4.
5.
6.
7.
8. 9.
10.
Aycicek A, Koc A, Abuhandan M (2010) Efficacy of deferasirox in children with β-thalassemia: single-center 3 year experience. Pediatr Int 56(4):530–3. doi:10.1111/ped.12323, Epub 2014 May 30 Cappellini MD, Bejaoui M, Agaoglu L, Canatan D et al (2011) Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years’ follow-up. Blood 118(4):884–93. doi:10.1182/blood-2010-11-316646, Epub 2011 May 31 Bruin GJ, Faller T, Wiegand H, Schweitzer A et al (2008) Pharmacokinetics, distribution, metabolism, and excretion of deferasirox and its iron complex in rats. Drug Metab Dispos 36(12):2523–38. doi:10.1124/dmd.108.022962, Epub 2008 Sep 5 Stingl JC, Bartels H, Viviani R, Lehmann ML, Brockmöller J (2014) Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: a quantitative systematic review. Pharmacol Ther 141(1):92–116. doi:10.1016/j.pharmthera.2013.09.002, Epub 2013 Sep 27. Review Han JY, Lim HS, Shin ES, Yoo YK et al (2006) Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol 24:2237–44, Epub 2006 Apr 24 Satoh T, Ura T, Yamada Y, Yamazaki K et al (2011) Genotype directed, dose-finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms. Cancer Sci 102: 1868–73. doi:10.1111/j.1349-7006.2011.02030.x, Epub 2011 Aug 12 Sakurai A, Tamura A, Onishi Y, Ishikawa T (2005) Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications. Expert Opin Pharmacother 6(14):2455–73, Review Rodríguez-Soriano J, Vallo A (1990) Renal tubular acidosis. Pediatr Nephrol 4(3):268–75, Review Papadopoulos N1, Vasiliki A, Aloizos G, Tapinis P, Kikilas A (2010) Hyperchloremic metabolic acidosis due to deferasirox in a patient with beta thalassemia major. Ann Pharmacother 44(1):219– 21. doi:10.1345/aph.1M440 Naranjo CA, Busto U, Sellers EM, Sandor P et al (1981) A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30(2):239–45
LETTER TO THE EDITORS
Deferasirox-induced serious adverse reaction in a pediatric patient: pharmacokinetic and pharmacogenetic analysis M. Marano 1 & G. Bottaro 2 & B. Goffredo 3 & F. Stoppa 1 & M. Pisani 4 & A. M. Marinaro 5 & F. Deodato 6 & C. Dionisi-Vici 6 & E. Clementi 7,8 & F. S. Falvella 9
Received: 4 September 2015 / Accepted: 18 September 2015 / Published online: 24 September 2015 # Springer-Verlag Berlin Heidelberg 2015
Keywords Deferasirox . Adverse events . Hyperchloremic metabolic acidosis . Hyperammonemia
We report the case of a 3-year-old girl affected by major thalassemia. She was treated with Deferasirox (DFR), an oral iron chelator, at the dosage of 33 mg/kg per day since the age of 2 years. During the following months, the child underwent three admissions for fever, vomiting, metabolic acidosis, increased azotemia and dehydration. One episode
* M. Marano [email protected] 1
DEA Intensive Care Unit, IRCCS BBambino Gesù^ Children Hospital, Piazza S. Onofrio 4, Rome 00165, Italy
2
Department of Pediatrics BTor Vergata University^, Rome, Italy
3
Laboratory of Analytical Biochemistry, IRCCS BBambino Gesù^ Children Hospital, Rome, Italy
4
DEA, IRCCS BBambino Gesù^ Children Hospital, Rome, Italy
5
Department of Pediatrics, Section of Pediatrics Haematology and Oncology, University of Sassari, Sassari, Italy
6
Department of Pediatric Medicine, Division of Metabolism, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
7
Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Lecco, Italy
8
Department of Biomedical and Clinical Sciences L. Sacco, Unit of Clinical Pharmacology, CNR Institute of Neuroscience, BLuigi Sacco^ University Hospital, University of Milano, Milan, Italy
9
Department of Biomedical and Clinical Sciences, Unit of Clinical Pharmacology, BLuigi Sacco^ University Hospital, University of Milano, Milan, Italy
was characterised by elevation of transaminases (AST 472 U/L, ALT 479 U/L). During this period, weight loss (from 15 to 12 kg) and behavioural changes were observed. After 1 month, the girl was admitted to a local hospital for vomiting, stuporous state, lockjaw, and myoclonus. The cerebral CT scan was normal. Exams showed elevated ammonia level in three determinations (741–744–536 mcg/dl), hypoglycemia (36 mg/dl), elevation of transaminases (AST 42 U/L, ALT 148 U/L) alkaline phosphatase 396 U/L, INR 1.36. DFR was discontinued. A urea cycle disorder was first suspected, protein intake was stopped, and intravenous glucose solution, arginine and sodium benzoate infusion was started. She was transferred to our PICU. On her arrival (20 h later), exams showed hyperchloremic metabolic acidosis (pH 7.19, Cl− 122 mmol/L, Lac 0.7 mmol/L, BE −17 mmol/L, HCO3− 11 mmol/L), anion gap 9 mmol/L, hypophosphoremia (1.5 mg/dl), normal ammonia and transaminases. Blood lactate, plasma amino acids and acylcarnitines were normal, while urinary organic acids analysis showed an increase of lactic, 3OH butyric, pyruvic, citric, succinic and fumaric acids. Glycosuria, proteinuria, hemoglobinuria, ketonuria and leucocyturia were present with increase of β2-microglobulin. Hemolytic uremic syndrome and sepsis were excluded. Because of the persisting metabolic acidosis and oligo-anuria, a continuous venovenous hemodialysis (CVVHD) treatment was started. The child had showed a progressive improvement and was discharged after 2 weeks. Even if DFR recommended dosage is 20–30 mg/kg per day, it has been reported that in transfused children, a good iron balance is achieved with DFR dosage ≥30 mg/kg per day [1]. Nevertheless, the European Medicines Agency has revealed an increase of adverse events (AE) with DFR dosage >30 mg/kg per day. In children, the commonest AE include vomiting, abdominal pain,
248 Table 1
Eur J Clin Pharmacol (2016) 72:247–248 Pharmacogenetic analyses performed in our case
Protein
Gene
UGT1A1
UGT1A1
Variant
Orientation strand
SNP ID
MAF
Functional effect
Case genotype
*6/c.211G>A
Forward
rs4148323
0.03
Decreased activity
GG
*28/(TA)6>(TA)7
Forward
rs8175347
0.32
Reduced expression
(TA)6TA)6
*60/-3279T>G *93/-3156G>A
Forward Forward
rs4124874 rs10929302
0.47 0.30
Reduced expression Reduced expression
TG GG
MRP2
ABCC2
c.-24C>T c.4544G>A
Forward Forward
rs717620 rs8187710
0.14 0.07
Decreased activity Impaired ATPase activity
CT GA
BCRP
ABCG2
c.421C>A
Reverse
rs2231142
0.12
Reduced protein levels
GG
Genotypes associated to a poor metabolizer or impaired transporter activity are italicized. For further and updated information on variants and population frequency please see http://www.ensembl.org/index.html or http://www.pharmacogenomics.pha.ulaval.ca/cms/ugt_alleles/ MAF minor allele frequency
transaminases and blood creatinine increase, fever, nausea, diarrhea and liver damage [2]. Given the possible association of the symptomatology of our patient with DFR assumption and considering the negativity of all other examinations, it was decided to evaluate the drug plasmatic concentration and perform a pharmacogenetic analysis. DFR is metabolised by uridine diphosphate glucuronosyltransferase (UGT) and eliminated into the bile through multidrug resistance protein 2 (MRP2) and breast cancer resistance protein (BCRP) [3]. Defective UGT1A1 alleles and polymorphisms of ABCC2 and ABCG2 coding for MRP2 and BCRP proteins may eventually contribute to the development of drug-related AE [4–7]. As reported in Table 1, our patient has been found carrier of UGT1A1 and ABCC2 polymorphisms explaining a possible reduction of DFR metabolism together with a reduction of biliary elimination by MRP2. Since MRP2 transports the drug also from the cells to the tubular lumen, an impaired transporter activity leads to intracellular drug accumulation with nephrotoxicity. Our patient presented glycosuria, proteinuria, hyperchloremic metabolic acidosis, hypophosphoremia and increased β2-microglobulin, all features compatible with renal proximal tubular injury [8, 9]. In our patient, hyperammonemia due to inborn errors of metabolism was ruled out. We assume that a reduced metabolism genetically determined might have caused an accumulation of DFR, confirmed by increased plasmatic levels (186 mg/ml, normal range 0.16–40). This could have caused a liver and kidney drug toxicity, also considering the exclusion of any other possible cause and the application of the Naranjo algorithm (score 10) [10]. This case highlights a potential risk of toxicity in subjects requiring iron-chelating therapy stressing the need for a close and careful monitoring.
References 1.
2.
3.
4.
5.
6.
7.
8. 9.
10.
Aycicek A, Koc A, Abuhandan M (2010) Efficacy of deferasirox in children with β-thalassemia: single-center 3 year experience. Pediatr Int 56(4):530–3. doi:10.1111/ped.12323, Epub 2014 May 30 Cappellini MD, Bejaoui M, Agaoglu L, Canatan D et al (2011) Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: efficacy and safety during 5 years’ follow-up. Blood 118(4):884–93. doi:10.1182/blood-2010-11-316646, Epub 2011 May 31 Bruin GJ, Faller T, Wiegand H, Schweitzer A et al (2008) Pharmacokinetics, distribution, metabolism, and excretion of deferasirox and its iron complex in rats. Drug Metab Dispos 36(12):2523–38. doi:10.1124/dmd.108.022962, Epub 2008 Sep 5 Stingl JC, Bartels H, Viviani R, Lehmann ML, Brockmöller J (2014) Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: a quantitative systematic review. Pharmacol Ther 141(1):92–116. doi:10.1016/j.pharmthera.2013.09.002, Epub 2013 Sep 27. Review Han JY, Lim HS, Shin ES, Yoo YK et al (2006) Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol 24:2237–44, Epub 2006 Apr 24 Satoh T, Ura T, Yamada Y, Yamazaki K et al (2011) Genotype directed, dose-finding study of irinotecan in cancer patients with UGT1A1*28 and/or UGT1A1*6 polymorphisms. Cancer Sci 102: 1868–73. doi:10.1111/j.1349-7006.2011.02030.x, Epub 2011 Aug 12 Sakurai A, Tamura A, Onishi Y, Ishikawa T (2005) Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications. Expert Opin Pharmacother 6(14):2455–73, Review Rodríguez-Soriano J, Vallo A (1990) Renal tubular acidosis. Pediatr Nephrol 4(3):268–75, Review Papadopoulos N1, Vasiliki A, Aloizos G, Tapinis P, Kikilas A (2010) Hyperchloremic metabolic acidosis due to deferasirox in a patient with beta thalassemia major. Ann Pharmacother 44(1):219– 21. doi:10.1345/aph.1M440 Naranjo CA, Busto U, Sellers EM, Sandor P et al (1981) A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30(2):239–45
