Factors for Hematopoietic Toxicity of Carboplatin: Refining the Targeting of Carboplatin Systemic Exposure

Purpose Area under the curve (AUC) dosing is routinely carried out for carboplatin, but the chosen target AUC values remain largely empirical. This multicenter pharmacokinetic-pharmacodynamic (PK-PD) study was performed to determine the covariates involved in the interindividual variability of carboplatin hematotoxicity that should be considered when choosing individual target AUCs.Patients and Methods Three hundred eighty-three patients received carboplatin as part of established regimens. A semi-physiologic population PK-PD model was applied to describe separately the time course of absolute neutrophil and platelet counts using NONMEM software. The plasma ultrafiltrable carboplatin concentration (CCarbo) was assumed to inhibit the proliferation of blood cell precursors through a linear model: drug effect = slope × CCarbo. The slope corresponds to the patients\u27 sensitivity to carboplatin hematotoxicity. The relationships between the patients\u27 sensitivity to the neutropenic or thrombopenic effects of carboplatin and various covariates, including associated chemotherapies, demographic, biologic, and pharmacogenetic data, were studied. Results The sensitivity of carboplatin-induced thrombocytopenia decreased in the case of concomitant paclitaxel chemotherapy (slope decreased by 24%), whereas it increased with coadministration of etoposide and gemcitabine (slope increased by 45% and 133%, respectively). For neutropenia, the sensitivity increased when carboplatin was combined with other cytotoxics (slope increased by 76%). Conclusion This study provides useful information to clinicians to better estimate the hematopoietic toxicity of carboplatin and thus choose more rationally carboplatin target AUCs as a function of pretreatment or concomitantly administered chemotherapies. For example, an AUC of 5 mg/mL · min is associated with a risk of grade 3 or 4 thrombocytopenia of 2% in combination with paclitaxel versus 38% with gemcitabine in a non-pretreated patient

Comparison of nonparametric methods in nonlinear mixed effects models

During the drug development, nonlinear mixed effects models are routinely used to study the drug's pharmacokinetics and pharmacodynamics. The distribution of random effects is of special interest because it allows to describe the heterogeneity of the drug's kinetics or dynamics in the population of individuals studied. Parametric models are widely used, but they rely on a normality assumption which may be too restrictive. In practice, this assumption is often checked using the empirical distribution of random effects' empirical Bayes estimates. Unfortunately, when data are sparse (like in patients phase III clinical trials), this method is unreliable. In this context, nonparametric estimators of the random effects distribution are attractive. Several nonparametric methods (estimators and their associated computation algorithms) have been proposed but their use is limited. Indeed, their practical and theoretical properties are unclear and they have a reputation for being computationally expensive. Four nonparametric methods in comparison with the usual parametric method are evaluated. Statistical and computational features are reviewed and practical performances are compared in simulation studies mimicking real pharmacokinetic analyses. The nonparametric methods seemed very useful when data are sparse. On a simple pharmacokinetic model, all the nonparametric methods performed roughly equivalently. On a more challenging pharmacokinetic model, differences between the methods were clearer.

Modeling buprenorphine reduction of fentanyl-induced respiratory depression

BACKGROUND. Potent synthetic opioids, such as fentanyl, are increasingly abused, resulting in unprecedented numbers of fatalities from respiratory depression. Treatment with the high-affinity mu-opioid receptor partial agonist buprenorphine may prevent fatalities by reducing binding of potent opioids to the opioid receptor, limiting respiratory depression. METHODS. To characterize buprenorphine-fentanyl interaction at the level of the mu-opioid receptor in 2 populations (opioid-naive individuals and individuals who chronically use high-dose opioids), the effects of escalating i.v. fentanyl doses with range 0.075???0.35 mg/70 kg (opioid naive) and 0.25???0.70 mg/70 kg (chronic opioid use) on iso-hypercapnic ventilation at 2???3 background doses of buprenorphine (target plasma concentrations range: 0.2???5 ng/mL) were quantified using receptor association/dissociation models combined with biophase distribution models. RESULTS. Buprenorphine produced mild respiratory depression, while high doses of fentanyl caused pronounced respiratory depression and apnea in both populations. When combined with fentanyl, buprenorphine produced a receptor binding???dependent reduction of fentanyl-induced respiratory depression in both populations. In individuals with chronic opioid use, at buprenorphine plasma concentrations of 2 ng/mL or higher, a protective effect against high-dose fentanyl was observed. CONCLUSION. Overall, the results indicate that when buprenorphine mu-opioid receptor occupancy is sufficiently high, fentanyl is unable to activate the mu-opioid receptor and consequently will not cause further respiratory depression in addition to the mild respiratory effects of buprenorphine. TRIAL REGISTRATION. Trialregister.nl, no. NL7028 (https://www.trialregister.nl/trial/7028) FUNDING. Indivior Inc., North Chesterfield, Virginia, USA

Tolerance to opioid-induced respiratory depression in chronic high-dose opioid users: a model-based comparison with opioid-naive individuals

Chronic opioid consumption is associated with addiction, physical dependence, and tolerance. Tolerance results in dose escalation to maintain the desired opioid effect. Intake of high-dose or potent opioids may cause life-threatening respiratory depression, an effect that may be reduced by tolerance. We performed a pharmacokinetic-pharmacodynamic analysis of the respiratory effects of fentanyl in chronic opioid users and opioid-naive subjects to quantify tolerance to respiratory depression. Fourteen opioid-naive individuals and eight chronic opioid users received escalating doses of intravenous fentanyl (opioid-naive subjects: 75-350 mu g/70 kg; chronic users: 250-700 mu g/70 kg). Isohypercapnic ventilation was measured and the fentanyl plasma concentration-ventilation data were analyzed using nonlinear mixed-effects modeling. Apneic events occurred in opioid-naive subjects after a cumulative fentanyl dose (per 70 kg) of 225 (n = 3) and 475 mu g (n = 6), and in 7 chronic opioid users after a cumulative dose of 600 (n = 2), 1,100 (n = 2), and 1,800 mu g (n = 3). The time course of fentanyl's respiratory depressant effect was characterized using a biophase equilibration model in combination with an inhibitory maximum effect (E-max) model. Differences in tolerance between populations were successfully modeled. The effect-site concentration causing 50% ventilatory depression, was 0.42 +/- 0.07 ng/mL in opioid-naive subjects and 1.82 +/- 0.39 ng/mL in chronic opioid users, indicative of a 4.3-fold sensitivity difference. Despite higher tolerance to fentanyl-induced respiratory depression, apnea still occurred in the opioid-tolerant population indicative of the potential danger of high-dose opioids in causing life-threatening respiratory depression in all individuals, opioid-naive and opioid-tolerant

Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients

BackgroundOpioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression.MethodsIn this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses >= 90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (V-E). Additionally, occurrence of apnea was recorded.ResultsFentanyl-induced changes in V-E were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced V-E by [LSmean (95% CI)] 26% (13-40%) and 47% (37-59%) compared to 51% (38-64%) and 79% (69-89%) during placebo infusion (p = 0.001 and < .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced V-E up to 49% (21-76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68-132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001).InterpretationResults from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl