PORT: A Randomized, Cross-Over, Phase 2 Study of Melflufen Peripheral Versus Central Intravenous Administration in Patients With Relapsed/Refractory Multiple Myeloma.

BACKGROUND: Melflufen, a first-in-class alkylating peptide-drug conjugate, rapidly enters tumor cells and metabolizes to melphalan. In previous studies, melflufen was administered via central venous catheter (CVC). However, administration by peripheral venous catheter (PVC) may be preferable. PATIENTS AND METHODS: PORT was a two-period, phase 2 crossover study of CVC versus PVC melflufen administration in patients with relapsed/refractory multiple myeloma. Adults with ≥ 2 prior therapies refractory to/intolerant of an immunomodulatory drug and a proteasome inhibitor were randomized 1:1 to weekly oral dexamethasone plus melflufen (40 mg) via CVC or PVC infusion on day 1 of 28-day cycle 1. In cycle 2, patients continued dexamethasone and crossed over to the other melflufen administration route. In cycle 3, all patients received melflufen until progression; PVC or CVC routes were allowed based upon investigator decision. Pharmacokinetic sampling was performed during and after melflufen infusion. Primary endpoints were melphalan pharmacokinetic parameters (Cmax, AUC(0-t), and AUC(0-∞)) and frequency and severity of PVC-related local reactions. RESULTS: The 90% CIs for adjusted geometric mean ratios for pharmacokinetic parameters following CVC versus PVC administration were within the 0.8-1.25 bioequivalence range (Cmax 0.946 [90% CI: 0.849, 1.053]; AUC(0-t) 0.952 [90% CI: 0.861, 1.053]; AUC(0-∞) 0.955 [90% CI: 0.863, 1.058]). In both arms, adverse events were primarily hematological and similar; no phlebitis or local infusion-related reactions occurred. CONCLUSION: Melflufen PVC and CVC administrations are bioequivalent based on melphalan pharmacokinetic parameters. Melflufen via PVC was well tolerated, with no infusion-related reactions or new safety signals and may represent an alternative route of administration.

Pharmacokinetics and Metabolism of Melflufen, an Alkylating Peptide-Drug Conjugate, in Patients with Relapsed Refractory Multiple Myeloma.

Melphalan flufenamide (melflufen) is a novel lipophilic peptide-drug conjugate recently approved in the European Union and the United Kingdom for the treatment of relapsed refractory multiple myeloma. Melflufen rapidly crosses the cell membrane, and inside tumor cells, melflufen utilizes peptidases and esterases to release entrapped hydrophilic metabolites with alkylating activity. In vitro, in whole blood, melflufen was rapidly distributed into blood cells and quickly converted to its main metabolite melphalan, with maximum cellular concentrations of noncovalently bound melflufen and melphalan after 1 and 6 minutes, respectively. Melphalan outflow from blood cells was slow, with peak concentrations in plasma after 25 minutes. The pharmacokinetics of melflufen was best described by a 2-compartment model. Following a 30-minutes intravenous infusion of 40 mg in 27 patients with relapsed refactory multiple myeloma, mean half-life in the α phase of the curve was 1.24 minutes, half-life in the ß phase of the curve 26.7 minutes, and clearance 13.4 L/min. Desethyl-melflufen exposure was below 20% compared to melflufen. Based on population analysis (298 patients with relapsed refactory multiple myeloma), the melphalan pharmacokinetics were well characterized by a 3-compartment model with melflufen dosing into a peripheral compartment, assuming instantaneous distribution of melflufen into cells and subsequent rapid metabolism to melphalan. Mean clearance and central and deep peripheral volumes of distribution were 22.4 L/h, 2.70 L, and 51.3 L, respectively. Clearance increased and maximum concentration decreased with increasing body weight and estimated glomerular filtration rate. In conclusion, melflufen administration differs from melphalan administration by a more rapid distribution into cells, which, in conjunction with a rapid intracellular metabolism, allows for higher maximum concentrations of alkylating agents, and by a more extensive distribution of melphalan to peripheral tissues.

The effect of a long term epidural infusion of ropivacaine on CYP2D6 activity.

BACKGROUND: Ropivacaine and one of its metabolites, pipecoloxylidide, inhibit CYP2D6 in. human liver microsomes in vitro with K(i) values of 5 microM (1.4 mg/L) and 13 microM (3.6 mg/L), respectively. We investigated the effect of a 50 h continuous epidural infusion of ropivacaine 2 mg/mL at a rate of 14 mL/h on CYP2D6 activity. METHODS: Nineteen patients (41-85 yr) undergoing hip or knee replacement, all extensive metabolizers with respect to CYP2D6 activity, were included. Medications known to inhibit or be metabolized by CYP2D6, or known to be strong inhibitors/inducers of CYP1A2 or CYP3A4 were not allowed. Patients received 10 mg debrisoquine (a marker for CYP2D6 activity) before surgery and after 40 h epidural infusion. The metabolic ratio (MR) for debrisoquine hydroxylation was calculated as the amount of debrisoquine/amount of 4-OH-debrisoquine excreted in 0-10 h urine. RESULTS: The median (range) of MR before and after ropivacaine were 0.54 (0.1-3.4) and 1.79 (0.3-6.7), respectively. The Hodges Lehman estimate of the ratio MR after/MR before ropivacaine was 2.2 with a 95% confidence interval 1.9-2.7 (P < 0.001). CONCLUSION: A continuous epidural infusion of ropivacaine inhibits CYP2D6 activity in patients who are extensive metabolizers resulting in a twofold increase in the MR for debrisoquine hydroxylation. However, since none of the patients was converted into a functional poor metabolizer (MR >12.6), the effect on the metabolism of other drugs metabolized by CYP2D6 is unlikely to be of major clinical importance.

Pharmacokinetics and efficacy of ropivacaine for continuous epidural infusion in neonates and infants.

INTRODUCTION: The primary objective of this noncomparative study was to evaluate the pharmacokinetics of ropivacaine during a 48-72-h continuous epidural infusion of ropivacaine in children under 1 year. The secondary objectives were to assess efficacy and safety. METHODS: Neonates and infants (ASA I-III, gestational age > or =37 weeks, > or =2.5 kg, scheduled for major abdominal or thoracic surgery) were included and separated into age groups: 0-30 (neonate), 31-90, 91-180, and 181-365 days. Ethics committee approval and informed parental consent were obtained before inclusion. An epidural catheter was introduced under general anesthesia at the appropriate dermatomal level. An initial bolus dose (0.9-2.0 mg.kg(-1) of ropivacaine 0.2%) was followed by an epidural infusion (0.2 mg.kg(-1).h(-1) for infants <180 days or 0.4 mg.kg(-1).h(-1) for infants >180 days). Plasma samples were collected every 12 h from 24 h, and on termination of the epidural infusion. Postoperative pain was evaluated using both the Objective Pain Scale and a four-graded descriptive scale. RESULTS: Forty-five infants, median age 116 (0-362) days, were included. Forty-three and 19 patients received an infusion for at least 48 and 72 h, respectively. Satisfactory analgesia was provided in the majority, only 20 patients were given supplementary medication during the infusion. In all age groups, plasma concentrations of unbound ropivacaine leveled at 24 h, without any further increase at 48 and 72 h. Because of lower clearance of unbound ropivacaine in neonates (mean 33 ml.min(-1).kg(-1)) than in infants above the age of 30 days (80, 124, and 163 ml.min(-1).kg(-1), respectively, in the age groups 31-90, 91-180, and 180-365 days), unbound ropivacaine concentrations at the end of infusion were higher in neonates [median 0.10 mg.l(-1) (0.04-0.21 mg.l(-1))] than in infants >30 days [median 0.03 mg.l(-1) (0.003-0.10 mg.l(-1))]. CONCLUSION: Epidural infusions (0.2-0.4 mg.kg(-1).h(-1) ropivacaine) provided satisfactory pain relief in neonates and infants under 1 year. As plasma concentrations of unbound ropivacaine were not influenced by the duration of the infusion, ropivacaine can be safely used for postoperative epidural infusion for 48-72 h. Levels of unbound ropivacaine were higher in the neonates than in the infants, but were below threshold concentrations for CNS toxicity in adults (> or =0.35 mg.l(-1)). This should not preclude the use of ropivacaine infusions in neonates but suggests a need for caution during the first weeks of life.

Ropivacaine in neonates and infants: a population pharmacokinetic evaluation following single caudal block.

BACKGROUND: The aims of this study were to evaluate pharmacokinetics, efficacy and safety of ropivacaine in infants aged 0-12 months following a single caudal injection. METHODS: Term ASA I-III patients, scheduled for surgery, with a body weight of > or = 2500 g received a caudal block with ropivacaine 2 mg x ml(-1), 1.0 ml x kg(-1). Plasma samples were collected at different time intervals up to 30 h, for analysis of total and unbound ropivacaine and alpha-1-acid glycoprotein (AAG). Pharmacokinetic data were characterized by population analysis. Unbound and total concentrations from 35 patients, median (min-max) postnatal age of 66 (4-351) days, were included in the nonlinear mixed effects modeling to provide estimates of pharmacokinetic parameters and the exploration of covariate relationships. Simulations were made to test the predictive performance of the final model and to describe the effect of significant covariates on systemic exposure. RESULTS: The mean (min-max) peak plasma concentration of total ropivacaine was 0.83 (0.05-1.57) mg x l(-1) at 0.5-5.7 h (median: 1.0 h) and the plasma concentration of unbound ropivacaine was 0.042 (0.012-0.081) mg x l(-1) within 0.5-1 h. The observed unbound fraction in plasma was 6% (1%-14%). A one-compartment open model with first-order absorption and elimination, incorporating a linear-binding model of ropivacaine to AAG best described the data. The only significant covariate relationship was that of age on Clu/F according to the following relationship Clu/F = 3.01 x e0.00474 x Age. This predicts a Clu/F of 3.5 l x h(-1) x kg(-1) at 30 days and 10.8 l x h(-1) x kg(-1) at 270 days with corresponding terminal half-lives of 6.7 and 2.2 h. The interindividual variability (coefficient of variation, CV) in Clu/F was 39%. The population estimate (CV) of ka was 1.65 h(-1) (30%), Vu/F was 33.6 (l x kg(-1)) (45%) and Ka was 1.78 l x mg(-1) (14%). Thirty-five infants received supplementary analgesics (mostly paracetamol). The median time to first supplementary analgesic (based on all 37 patients) was 3.9 h. No safety concerns or signs of systemic toxicity were observed. CONCLUSIONS: Following a caudal block with ropivacaine 2 mg x kg(-1) plasma concentrations of unbound ropivacaine were well below threshold levels for toxicity in adults. Apparent volume of distribution is unchanged, apparent unbound clearance increases and the terminal half-life decreases with age in 0-12-month-old neonates and infants. The postoperative pain management provided adequate analgesia and was well tolerated.

Continuous interscalene analgesia with ropivacaine 2 mg/ml after major shoulder surgery.

BACKGROUND: In this open, randomized study, the pharmacokinetics, clinical efficacy, and safety of a 48-h continuous interscalene infusion of 2 mg/ml ropivacaine for postoperative pain relief were investigated in patients undergoing open major shoulder surgery. METHODS: An initial interscalene block with 30 ml ropivacaine, 7.5 mg/ml (225 mg), was performed. After completion of interscalene block, all patients (n = 24) received general anesthesia, and 6 h after interscalene block, a 48-h continuous interscalene infusion of 12 or 18 mg/h using 2 mg/ml ropivacaine was started. Total and unbound plasma concentrations of ropivacaine and 2.6-pipecoloxylidide (PPX; a major active metabolite) were determined during and up to 6 h after the interscalene infusion. Postoperative pain at rest was assessed by a visual analog scale. Supplementary analgesics and adverse events were recorded. RESULTS: Plasma concentrations of total and unbound ropivacaine were proportional to the total dose. At the end of the interscalene infusion of 9 ml/h, the mean +/- SD plasma concentrations of total and unbound ropivacaine were 1.40 +/- 0.54 and 0.03 +/- 0.01 mg/l, respectively, and of total and unbound PPX were 0.70 +/- 0.38 and 0.30 +/- 0.20 mg/l, respectively. Plasma concentrations of unbound ropivacaine and unbound PPX, added together, remained well below threshold levels for systemic central nervous system toxicity. There were no significant differences between the groups for postoperative pain (median maximum of about 20 mm on the visual analog scale in both groups), analgesic consumption, or quality of pain relief assessed by the patient. No signs or symptoms of systemic local anesthetic toxicity were observed. CONCLUSION: A 48-h continuous interscalene infusion of 6 or 9 ml/h ropivacaine, 2 mg/ml, started 6 h after an initial interscalene block of 30 ml ropivacaine, 7.5 mg/ml, provided satisfactory postoperative pain relief after major shoulder surgery and was well tolerated. Unbound plasma concentrations of ropivacaine and PPX remained well below threshold levels for systemic central nervous toxicity.