Our results are in agreement with the in vitro data concerning the extensive binding of oxaliplatin to plasma proteins and RBCs. They also reveal a strong negative correlation between free drug plasma availability and renal function, with a corresponding positive correlation between clearance of the plasmatic platinum and renal function. Thus, renal impairment entails a greater overall exposure to platinum in the plasma. However, this study failed to elicit any relationship between moderate renal impairment and the acute toxicity associated with oxaliplatin.

Oxaliplatin is the first clinically available diaminocyclohexane platinum coordination complex. The drug is non-cross-resistant with cisplatin or carboplatin and is one of the few active drugs against human colorectal cancer. Its cytotoxicity is synergistic with fluorouracil and folinic acid (leucovorin), the reference treatment for this disease. The main cumulative dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy. The drug can also produce diarrhoea, vomiting and haematological suppression. Unlike cisplatin, no renal failure or peripheral motor neuropathy have been reported and the sensory neuropathy is partly reversible. Unlike carboplatin, oxaliplatin produces only mild to moderate haematological toxicity. Oxaliplatin undergoes biotransformation into aquated forms in the blood, where 3 species can be found: total platinum, ultrafilterable or 'free' platinum and erythrocyte platinum. Flameless atomic absorption (FAAS) is used for assaying platinum concentration in various tissues. Inductively-coupled plasma mass spectrometry (ICP-MS), with a >10-fold lower sensitivity threshold than FAAS, was also used for the determination of oxaliplatin pharmacokinetics. The pharmacokinetics of oxaliplatin are described by a 3-compartment model. The drug rapidly crosses the cellular membrane as a result of its lipophilicity. Hence, at the end of a 2-hour infusion, approximately 40% of the blood platinum is found in erythrocytes. The distribution half-life of ultrafiltrated plasma platinum ranges from 10 to 25 minutes and its terminal elimination half-life is 26 hours (determined with FAAS) or 270 hours (ICP-MS). The elimination half-life of erythrocytic platinum is 12 to 50 days, close to that of erythrocytes. 30 to 50% of the platinum is recovered in the urine within 2 to 5 days, with renal clearance accounting for half of the total clearance of ultrafiltrated platinum. The total clearance of this species is correlated with the glomerular filtration rate. No pharmacokinetic-pharmacodynamic relationship has been established for oxaliplatin. Pharmacokinetic alterations produced by fluorouracil + folinic acid or irinotecan were minimal if any. The prolonged stability of oxaliplatin makes it suitable for continuous infusions over 4 to 5 days, with a delivery rate which can be either constant or chronomodulated (peak rate at 1600h), using programmable ambulatory pumps. Chronomodulation significantly reduces toxicity and improves antitumour activity as compared with constant rate infusion. These differences in pharmacodynamic properties were paralleled by differences in plasma concentration time courses. The different drug concentration profiles achieved with different infusional modalities may be useful tools for understanding the relationship between the pharmacokinetics and pharmacodynamics of oxaliplatin and may lead to further optimisation of its administration schedule and its combination with other drugs.

Pharmacokinetics of total platinum, 5-fluorouracil, l-folinic and d-folinic acid, and 5-methyltetrahydrofolate were studied in plasma from nine patients with advanced colorectal cancer treated with oxaliplatin (20 mg/m2/day), 5-fluorouracil (600 mg/m2/day), and folinic acid (300 mg/m2/day). Drugs were administered with a programmable-in-time pump by continuous infusion for 5 days. We compared two drug delivery schedules: constant rate versus chronomodulated rate with peak of oxaliplatin at 4 pm and peak of 5-fluorouracil and folinic acid at 4 am. In the chronomodulated schedule, plasma concentrations of the drugs paralleled the pump functioning: maximum platinum concentration near 4 pm, and maximum 5-fluorouracil and folate concentrations near 4 am. When drugs were administered at a constant rate, mean plasma concentration of 5-fluorouracil varied in a circadian manner each treatment day, that is, a peak at 4 am (approximately 800 ng/ml) and a trough at 1 pm (approximately 100 ng/ml). Mean plasma levels of total platinum and folate compounds increased over the first 24 hours. Total platinum mean level and that of the inactive d-folinic acid isomer reached a constant plasma concentration, whereas biologically active folates exhibited circadian variation in their plasma concentrations (peak around 7 am, trough near 6 pm, and amplitude approximately 10%). Severe mucositis was exhibited by all four patients on the flat schedule, but only by one on the chronomodulated schedule (p < 0.008). Individual pharmacokinetic and toxicity data showed that patients with circadian rhythms in 5-fluorouracil concentrations were least sensitive to 5-fluorouracil-related toxicity. Thus amplification or induction of such rhythm in 5-fluorouracil exposure may permit dose escalation.

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BackgroundSystemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by a wide spectrum of manifestations, potentially involving every system. This heterogeneity may influence different aspects of patients’ daily life, including physical ability, working and social life, thus impacting the quality of life (QoL). Among all the SLE-related manifestations, cutaneous involvement may lead to insecurity and isolation, negatively resulting in QoL.ObjectivesThe aim of the present study was to analyse the QoL in a SLE cohort, determining the potential influence of disease activity, chronic damage, comorbidities, and mood disorders.MethodsWe enrolled consecutive SLE patients, diagnosed according to 2019 ACR/EULAR criteria. Clinical and laboratory data were collected, and disease activity and chronic damage were assessed by SLEDAI-2k and SDI. As controls, we enrolled patients affected by Discoid Lupus Erythematosus (DLE) and Undifferentiated Connective Tissue Disease (UCTD). The fibromyalgia diagnosis was made according to the 2016 ACR Classification Criteria. Quality of life was evaluated by using the Lupus Quality of Life questionnaire (LupusQoL); furthermore, each patient filled out the Hospital Anxiety and Depression Scale (HADS) questionnaire.ResultsWe enrolled 237 SLE patients (M/F 18/219; median age 46 years [IQR 19.5], median disease duration 156 months [IQR 180]), 24 CLE patients (M/F 5/19; median age 61.5 years [IQR 29.5], median disease duration 92.1 months, [IQR 128.5]). and 25 UCTD (M/F 1/24; median age 40 years, [IQR 21.25]; median disease duration 66 months [QR 103.9]). In SLE patients the median SLEDAI-2k value was 0 (IQR 2) and the SDI was 0 (IQR 1). Fibromyalgia was diagnosed in 69 SLE patients (29.1%), 5 CLE (20.8%), and 7 UCTD (28%). The comparison among these three groups of patients revealed for SLE and CLE patients a significantly lower mean values in the LupusQoL domain related to Body Image (BI) (73.9±27.7 and 71.3±30.9, respectively) compared to UCTD patients (87.2±19.0) [p=0.01 and p=0.03, respectively]. Focusing on SLE patients, females showed significantly lower mean values compared to males for almost all domains: Pain (P, [p=0.02]), Intimate Relationship (IR; [p=0.001]), Burden to Others (BtO [p=0.029]), Emotional Health (EH; [p=0.012]), Body Image (BI; [p=0.033]) and Fatigue (F; [p=0.002]). As expected, fibromyalgia patients had lower values in all the domains of the LupusQoL when compared to patients without this condition (p<0.001 for all comparisons, except for BI p=0.006). Moreover, as reported in Figure 1, SDI values negatively correlated with all the LupusQoL domains (Figure 1A); conversely, we found a positive correlation between SDI and both HADS domains (Anxiety [r=0.16; p=0.015]; Depression [r=0.21; p=0.0009]). As expected, a strong negative correlation was identified between LupusQoL score in each domain and both Anxiety [(BH r=-0,58, P p=-0.53, Planning p=-0.52, IR p=-0.62, EH= -0.75, BI= -0.52, F=-0.64, BtO r=-0.62); p < 0.0001 for all the analysis] and Depression [(BH r=-0,61, P p=-0.58, Planning p=-0.63, IR p=-0.61, EH= -0.55, BI= -0.60, F=-0.69, BtO r=-0.55]; p < 0.0001 for all the analysis).ConclusionThe presented results confirmed the negative impact of SLE on the quality of life. Among the analyzed variables, female sex and fibromyalgia deeply influenced the outcome. The chronic damage showed to be one of the main determinants of impairment of the QoL in SLE patients and of the development of Anxiety and Depression, measured through the HADS questionnaire. Lastly, Anxiety and Depression may contribute to the worst QoL in SLE, underlying the need for comprehensive evaluation and management of the SLE-associated comorbidities.Figure 1.Correlations between HADS and LupusQoL domainsREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.