M. Bannink

Serum amino acids, biopterin and neopterin during long-term immunotherapy with interferon-alpha in high-risk melanoma patients

Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. One of the presumed pathophysiological mechanisms is an effect on tryptophan metabolism. As tryptophan is the precursor of serotonin, decreased availability of tryptophan to the central nervous system could result in serotonin deficiency. Tetrahydrobiopterin (BH((4))) is a cofactor for one of the enzymes synthesizing serotonin. We conducted an exploratory study into the serum concentrations of large neutral amino acids (AA), biopterin (BIOP) and neopterin (NEOP), of 67 patients with high-risk melanoma, who were either treated with two different doses of IFN-alpha or were part of an observation-only control group. We found evidence for IFN-alpha to decrease concentrations of all AA except phenylalanine. The decrease in tryptophan concentration was most prominent and consistent. These changes persisted throughout a year of maintenance treatment. Concentrations of NEOP rose sharply, whereas, those of BIOP did not change. Except for the increase in NEOP and the increase in the ratio between phenylalanine (PHE) and tyrosine (TYR), no support for derangement in BH((4)) metabolism was found. The increase in the ratio between PHE and TYR suggests inhibition of the enzyme phenylalanine hydroxylase. Patients with IFN-alpha induced anxiety and depression had higher pretreatment concentrations of NEOP. Changes in tryptophan metabolism may play a role in the pathophysiology of the neuropsychiatric side effects of IFN-alpha, and further research into the predictive potential of NEOP is warranted.

Influence of pegylated interferon-α therapy on plasma levels of citrulline and arginine in melanoma patients

Summary.The aim of this study was to evaluate the effect of pegylated interferon-alpha (PEG-IFN-α) on the plasma citrulline/arginine ratio, regarded as an index of nitric oxide (NO) synthesis, in patients with high-risk melanoma. Forty patients were randomly assigned to either PEG-IFN-α treatment (n = 22) or to observation only (control group, n = 18). The treatment group received 6 µg PEG-IFN-α/kg once a week during 8 weeks, followed by a maintenance dose of 3 µg/kg/wk. Blood was collected at different time points, plasma concentrations of citrulline and arginine were measured and the ratio of citrulline/arginine was calculated. Patients treated with PEG-IFN-α showed a significant decrease in the concentrations of citrulline and in the citrulline/arginine ratio during the whole study period, both compared to baseline values and to the control group. The data suggest that therapy with PEG-IFN-α results in a marked decrease in the synthesis of NO in melanoma patients.

Serum Activity of Prolyl Endopeptidase, but Not of Dipeptidyl Peptidase IV, Is Decreased by Immunotherapy with IFN-α in High-Risk Melanoma Patients

Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. In hepatitis patients treated with IFN-alpha, severity of depression correlates with a decrease in serum activity of dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5), a membrane-bound protease involved in the cleavage of cytokines and neuroactive peptides. Abnormal serum activity of the cytosolic peptidase prolyl endopeptidase (PEP, EC 3.4.21.26, postprolyl cleaving enzyme, prolyl oligopeptidase) has been documented in patients with a variety of psychiatric disorders, most consistently in mood disorders. The serum activity of PEP and DPP-IV was measured before and after 4 weeks of high-dose induction treatment with IFN-alpha in 18 patients with high-risk melanoma. In this exploratory study, we show a clear decrease in the serum activity of PEP after 4 weeks of treatment with IFN-alpha. This decrease was not related to changes in hematologic parameters. In contrast, serum activity of DPP-IV did not change. Further studies focusing on a possible role of PEP in the pathophysiology of IFN-alpha-induced depression are warranted.

Plasma activity of prolyl endopeptidase in relation to psychopathology during immunotherapy with IFN-alpha in patients with renal cell carcinoma.

Abnormal activity in peripheral blood of the cytosolic enzyme prolyl endopeptidase (PEP, EC 3.4.21.26, post prolyl cleaving enzyme, prolyl oligopeptidase) has been found in patients with a variety of psychiatric disorders, most consistently in mood disorders. Mood disturbance is a well-known side effect of immunotherapy with interferon-alpha (IFN-alpha). Earlier, we documented a decrease in serum PEP activity in the first 4 weeks of treatment with IFN-alpha. In 24 patients (16 men, 8 women, median age 60.5 years, range 47-72 years) with metastatic renal cell carcinoma (RCC), psychiatric assessment and blood sampling were performed before and at 4 and 8 weeks and at 6 months after initiation of treatment with IFN-alpha. No episodes of depression were observed, and the sum score and the scores on the subscales for depression and hostility of the Symptom Check List-90 (SCL-90) did not change during follow-up, whereas the anxiety scores were somewhat lower at 4 and 8 weeks compared with baseline. No change in plasma PEP activity and no relationships between change in psychiatric parameters and change in plasma PEP activity were found. As more subtle relationships between PEP activity and psychiatric status could have easily been obscured, a role for PEP in the pathophysiology of IFN-alpha-induced mood disturbance can neither be confirmed nor excluded.

322PFIRST INTRA-PATIENT COMPARISON OF ANTIDEPRESSANT USE AMONG TAMOXIFEN PATIENTS

ABSTRACT Aim: The anti-estrogen tamoxifen (Tam) requires activation to endoxifen by cytochrome P450 (CYP) enzymes. The use of potent CYP2D6-inhibiting drugs can significantly disrupt endoxifen formation, which probably affects the efficacy of Tam. For this reason, the use of potent CYP2D6-inhibiting antidepressants (AD) along with Tam is discouraged. However, this combination is still frequently used (Binkhorst et al, BCRT 2013). We studied the feasibility of switching potent CYP2D6-inhibiting AD to the mild CYP2D6 inhibitor escitalopram. Methods: Women receiving Tam in combination with a potent CYP2D6-inhibiting AD (paroxetine or fluoxetine), for at least 4 weeks, underwent blood sampling for pharmacokinetics (PK) during a 24h period. Patients were then switched to a mild CYP2D6-inhibiting AD by the psychiatrist. After 4 weeks, patients underwent a second PK sampling period. A validated LC-MS/MS method was used for quantification and PK parameters were calculated. Results: All included patients were successfully switched (cross-tapering) from paroxetine or fluoxetine to escitalopram, without any adverse effects or psychiatric relapse. During escitalopram treatment, the area under the curves (AUC0-24) of the active metabolites 4OH-Tam and endoxifen were significantly higher than during paroxetine/fluoxetine treatment. The median endoxifen AUC0-24 increased by 324% (n = 7; 445 nM*h (range 175-637) vs 105 nM*h (range 70-210); p= 0.018; Wilcoxon signed-rank test) and that of 4OH-Tam by 39% (90.2 nM*h (range 51.1-148) vs 65.0 nM*h (range 27.4-98.2); p= 0.028). Ratios of endoxifen/ND-Tam and 4OH-Tam/Tam increased by ∼3.4 and ∼1.4-fold, respectively. Conclusions: Switching from a potent CYP2D6-inhibiting AD to a weaker variant in women receiving Tam resulted in dramatic effects on endoxifen exposure. After switching, endoxifen concentrations were similar to that observed in our reference population of TAM-using women without CYP2D6-inhibiting co-treatment. The increase in metabolic ratios reflects higher CYP2D6 activity. No negative effects on the psychiatric treatment with AD were noticed. These data suggest that escitalopram, and probably other mild CYP2D6 inhibitors, is a safe and effective alternative in Tam-users. Disclosure: All authors have declared no conflicts of interest.