Cisplatin and carboplatin pharmacokinetics in a pediatric patient with hepatoblastoma receiving peritoneal dialysis.

PURPOSE: Cisplatin and carboplatin are frequently used drugs in the treatment of pediatric hepatoblastoma. Dosing guidelines for these drugs in children requiring peritoneal dialysis are lacking. Here, we describe the case of a 3-year-old boy with pre-existing end-stage renal disease on peritoneal dialysis, requiring treatment with cisplatin and carboplatin for hepatoblastoma. METHODS: Pharmacokinetic data were generated to support clinical dosing decisions, with the aim of adequate exposure and minimal toxicity. In the first chemotherapy cycle, 25% of the standard cisplatin dose and 75% of the carboplatin dose, calculated using the pediatric Calvert formula, were administered. Free platinum concentrations were determined in plasma ultrafiltrate and dialysate samples drawn after administration of cis- and carboplatin. RESULTS: Cisplatin was well tolerated and the observed AUC of cisplatin were 15.3 and 14.3 mg/L h in cycles 1 and 3, respectively. The calculated AUC of carboplatin in cycle 1 (9.8 mg/mL min) exceeded target AUC of 6.5 mg/mL min and toxicity was observed; therefore, the dose was reduced in cycles 2 and 3. The observed AUC in cycles 2 and 3 was 5.4 and 5.7 mg/mL min respectively. Platinum concentrations in the dialysate showed that 3-4% of the total dose of cisplatin and 10-12% of the total dose of carboplatin were excreted via peritoneal dialysis. Chemotherapy enabled extended hemihepatectomy and complete remission was achieved. CONCLUSION: This report shows that it is feasible to measure AUCs for both drugs and to individualize the dose of these drugs according to the PK results and clinical parameters. Our advice for future cases would be to calculate the starting dose of carboplatin using the (pediatric) Calvert formula, assuming a dialytic clearance of zero, and to adjust the dose if required, based on therapeutic drug monitoring.

Metformin and daclatasvir: absence of a pharmacokinetic-pharmacodynamic drug interaction in healthy volunteers.

AIM: The aim of the present study was to evaluate the effect of the proposed organic cation transporter (OCT) inhibitor daclatasvir on the pharmacokinetics and pharmacodynamics of the OCT substrate metformin. METHODS: This was an open-label, two-period, randomized, crossover trial in 20 healthy subjects. Treatment A consisted of metformin and treatment B consisted of metformin + daclatasvir. Pharmacokinetic curves were recorded at steady-state. Geometric mean ratios (GMRs) with 90% confidence intervals (CIs) were calculated for metformin area under the concentration-time curve from 0 h to 12 h (AUC0-12 ), maximum plasma concentration (Cmax ) and final plasma concentration (Clast ). An oral glucose tolerance test was performed, measuring insulin, glucose and lactate levels. RESULTS: The GMRs (90% CI) of metformin AUC0-12 , Cmax and Clast (B vs. A) were 109% (102-116%), 108% (101-116%) and 112% (103-122%). The geometric mean AUC0-2 for insulin, glucose and lactate during treatments A and B were 84 h. mEl-1 and 90 h. mEl-1 , 13.6 h. mmol l-1 and 13.4 h. mmol l-1 , and 3.4 h. mmol l-1 and 3.5 h. mmol l-1 , respectively. CONCLUSIONS: Bioequivalence analysis showed that daclatasvir does not influence the pharmacokinetics of metformin in healthy subjects. Pharmacodynamic parameters were also comparable between treatments.

Pharmacokinetics, Efficacy, and Safety of Hepatitis C Virus Drugs in Patients with Liver and/or Renal Impairment.

Hepatitis C virus (HCV)-infected patients often suffer from liver cirrhosis, which can be complicated by renal impairment. Therefore, in this review we describe the treatment possibilities in HCV patients with hepatic and renal impairment. Cirrhosis alters the structure of the liver, which affects drug-metabolizing enzymes and drug transporters. These modifications influence the plasma concentration of substrates of drugs metabolized/transported by these enzymes. The direct-acting antivirals (DAAs) are substrates of, for example, cytochrome P450 enzymes in the liver. Most DAAs are not studied in HCV-infected individuals with decompensated cirrhosis, and therefore awareness is needed when these patients are treated. Most DAAs are contraindicated in cirrhotic patients; however, patients with a Child-Pugh score of B or C can be treated safely with a normal dose sofosbuvir plus ledipasvir or daclatasvir, in combination with ribavirin. Patients with renal impairment (glomerular filtration rate [GFR] <90 mL/min) or who are dependent on dialysis often tolerate ribavirin treatment poorly, even after dose adjustments. However, most DAAs can be used at the normal dose because DAAs are not renally excreted. To date, grazoprevir plus elbasvir is the preferred DAA regimen in patients with renal impairment as data are pending for sofosbuvir patients with GFR <30 mL/min (as for ledipasvir and velpatasvir). However, sofosbuvir has been used in a small number of patients with severe renal impairment and, based on these trials, we recommend sofosbuvir 400 mg every day when no other DAA regimen is available. Ledipasvir and velpatasvir are not recommended in patients with severe renal impairment.

Natural history and treatment of HCV/HIV coinfection: Is it time to change paradigms?

Evidence over the past decades have shown that HIV/HCV coinfected patients did not respond as well to HCV therapy as HCV mono-infected patients. However, these paradigms are being recently reassessed with the improvements of care for HIV and HCV patients. This article reviews these original paradigms and how the new data is impacting upon them. Treatment efficacy now appears comparable for HIV/HCV coinfected and HCV mono-infected patients, while liver fibrosis progression is increasingly similar in optimally managed patients. Additional importance of therapy is directed to drug-drug interactions and the impact of HCV reinfection, as well as the possibility of transmitted drug resistance.

Lower Ribavirin Plasma Concentrations in HCV/HIV-Coinfected Patients Than in HCV-Monoinfected Patients Despite Similar Dosage.

BACKGROUND: Hepatitis C virus (HCV)/HIV-coinfected patients respond worse to dual therapy with ribavirin (RBV)/peginterferon compared with HCV-monoinfected patients. Several trials found that lower RBV plasma concentrations are associated with impaired virological response rates. The aim of this study was to determine RBV plasma concentrations in a cohort of HCV-monoinfected and HCV/HIV-coinfected patients. Our hypothesis is that HCV/HIV-coinfected patients have lower RBV plasma concentrations, which may in part explain their inferior response to dual therapy. METHODS: A retrospective cohort study was performed in chronic HCV-monoinfected and HCV/HIV-coinfected patients who received peginterferon and weight-based RBV. Plasma RBV concentrations were determined at weeks 4 and 12 by a validated high-performance liquid chromatography assay. RBV concentrations were compared between monoinfected and coinfected patients. We calculated the proportion of patients with a subtherapeutic RBV plasma concentration defined as <2.0 mg/L. RESULTS: A total of 61 HCV-infected patients were included, of whom 21 (34%) were coinfected with HIV. Although there was no difference in the weight-based dose of RBV between monoinfected and coinfected patients, RBV exposure was significantly lower in HCV/HIV-coinfected patients than in HCV-monoinfected patients: the mean ± SD RBV plasma concentrations were 1.82 ± 0.63 mg/L versus 2.25 ± 0.80 mg/L (P = 0.04) at week 4 and 2.14 ± 0.65 mg/L versus 2.62 ± 0.81 mg/L (P = 0.05) at week 12, respectively. The percentage of patients with subtherapeutic plasma concentrations of RBV in coinfected patients versus monoinfected patients was 62% versus 46% (P = 0.240) at week 4 and 50% versus 16% (P = 0.01) at week 12 of treatment, respectively. CONCLUSIONS: HIV/HCV-coinfected patients yield significantly lower plasma concentrations of RBV than HCV-monoinfected patients. This puts them at an increased risk of not achieving sustained virological response.

Determination of the HCV Protease Inhibitor Telaprevir in Plasma and Dried Blood Spot by Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Telaprevir is a protease inhibitor used in the treatment of hepatitis C virus infection. Analytical methods for telaprevir should separate the compound from its R-diastereomer VRT-127394, which is 30-fold less active. The objective of this work was to develop liquid chromatography-tandem mass spectrometer (LC-MS/MS) assays for telaprevir both in plasma and in dried blood spot (DBS), capable of stabilizing the equilibrium and chromatographically separating the 2 epimers. METHODS: Human plasma was acidified with formic acid and frozen within 1 hour after collection to stabilize the equilibrium between the 2 telaprevir diastereomers ex vivo in plasma. After protein precipitation, the sample was analyzed with LC-MS/MS. For the DBS assay, sampling paper was impregnated with citric acid solution to achieve stabilization of the epimers on the sampling paper. DBS samples were extracted before LC-MS/MS analysis. LC-MS/MS analysis comprised online solid-phase extraction and separation on a C18 column, with the mass spectrometer operating in TurboIonSpray-negative ionization mode and performing multiple reaction monitoring. RESULTS: The assays were linear over the concentration range of 0.1-10 mg/L in plasma and DBS. Accuracies ranged from 97% to 106% in plasma and from 93% to 99% in DBS. Within- and between-day coefficients of variation were <7.9% in plasma and <9.3% in DBS. Human whole blood samples with hematocrit values of 27%-47% gave reproducible quantitation results in the DBS assay, and spot volume did not affect results of the DBS assay either. Acidified plasma with telaprevir was stable for 5 hours at 20°C, and telaprevir on impregnated DBS paper was stable for at least 3 months at 4°C or at 20°C. CONCLUSIONS: An assay was developed and validated for the determination of telaprevir in human plasma, separating telaprevir from its R-diastereomer VRT-127394. In addition, a DBS assay was developed, which avoids immediate centrifuging, acidification, and freezing of patient samples to stabilize the equilibrium between the 2 telaprevir diastereomers.

The ARRIBA concept: adequate resorption of ribavirin.

BACKGROUND: Adequate ribavirin exposure is essential for optimal sustained virological response (SVR) rates in chronic HCV treatment. It has been proposed that the area under the concentration-time curve up to 4 h after intake of ribavirin (AUC0-4 h) of the first weight-based ribavirin dose should be ≥1.755 mg•h/l to guarantee the highest chance of SVR. Our ARRIBA concept comprises a test dose of ribavirin to select the optimal starting dose to achieve adequate exposure. This study aims to evaluate whether adequate exposure can be achieved after dose advice based on the AUC0-4 h of a single weight-based ribavirin test dose. METHODS: (Formerly) HCV-infected subjects received a single weight-based ribavirin test dose (<75 kg: 400 mg; ≥75 kg: 600 mg) and the AUC0-4 h was calculated. If ribavirin AUC0-4 h was ≥1.755 mg•h/l, subjects received the same dose 4 weeks later; if the AUC0-4 h was <1.755 mg•h/l, an adjusted dose was administered. The ribavirin AUC0-4 h was recorded again. The primary outcome was the proportion of subjects with an AUC0-4 h ≥1.755 mg•h/l after the second dose. RESULTS: A total of 26 subjects were included. The geometric mean (95% CI) ribavirin AUC0-4 h was 1.67 (1.44-1.92) mg•h/l with 9 subjects (35%) reaching the target AUC on day 1. Thus, on day 29, 17 subjects (65%) received an adjusted dose. The geometric mean (95% CI) AUC0-4 h increased to 1.90 (1.62-2.21) mg•h/l and then 16 subjects (62%) had an AUC0-4 h ≥1.755 mg•h/l, which is significantly higher than day 1 (P<0.05). CONCLUSIONS: Our ARRIBA concept of a ribavirin test dose, with dose adjustment if necessary, leads to an increased proportion of patients with an AUC≥1.755 mg•h/l compared to traditional weight-based ribavirin dosing.

Viral hepatitis C therapy: pharmacokinetic and pharmacodynamic considerations.

Chronic hepatitis C is a global health problem. To prevent or reduce complications, the hepatitis C virus (HCV) infection needs to be eradicated. There have been several developments in treating these patients since the discovery of the virus. As of 1 January 2014, the drugs that are approved for treatment of chronic HCV infection are peginterferon-α, ribavirin, boceprevir, telaprevir, simeprevir and sofosbuvir. In this review we provide an overview of the clinical pharmacokinetic characteristics of these agents by describing their absorption, distribution, metabolism and excretion. In the pharmacodynamic part we summarize what is known about the relationships between the pharmacokinetics of each drug and efficacy or toxicity. We briefly discuss the pharmacokinetics and pharmacodynamics of chronic hepatitis C treatment in special patient populations, such as patients with liver cirrhosis, renal insufficiency or HCV/HIV coinfection, and children. With this knowledge, physicians, pharmacists, nurse practitioners, etc. should be educated to safely and effectively treat HCV-infected patients.

Measuring ribavirin concentrations during the earliest stages of antiviral therapy for hepatitis C: potential relevance for treatment outcome.

BACKGROUND: Correlations between ribavirin (RBV) concentrations and sustained virological response (SVR) to hepatitis C virus treatment have been demonstrated previously. As steady state is reached after several weeks of RBV treatment, dose modifications based on steady-state levels can only be applied relatively late in treatment, possibly too late to influence SVR rates. The authors aimed to determine whether measurement of early concentrations is useful to predict optimal steady-state RBV concentrations. METHODS: In 61 treatment-naive genotype 1/4 patients RBV concentrations were determined in samples collected after 1, 2, 4, 8, 12, and 24 weeks of therapy. RBV concentrations were compared between responders and nonresponders; Receiver Operating Characteristic analyses were conducted to find optimal cut-off values to predict week 8 concentrations from earlier measurements. RESULTS: Median week 8 RBV concentrations were significantly higher in patients with SVR compared with those without: 3.4 (interquartile range 2.4-3.9) versus 2.6 (interquartile range 2.0-3.5) mg/L (P < 0.05). RBV concentration at week 8 was an independent predictor of SVR [adjusted odds ratio 2.3 (95% confidence interval: 1.1-4.9; P = 0.03)]. The optimal cut-off value of week 8 RBV concentration to predict SVR was 2.20 mg/L [sensitivity 87%, specificity 40%, positive predictive value 64%, negative predictive value 71%]. Optimal cut-off values at weeks 1, 2, or 4 to predict an RBV concentration ≥2.20 mg/L at week 8 were 0.92, 1.29, and 1.67 mg/L, respectively, with positive predictive values and negative predictive values ranging from 88% to 91% and 71% to 86%, respectively. CONCLUSIONS: RBV concentrations in the earliest stages of antiviral therapy predict therapeutic steady-state concentrations, allowing timely dose adjustments with potential implications for treatment outcome.

Lack of a clinically significant drug-drug interaction in healthy volunteers between the HCV protease inhibitor boceprevir and the proton pump inhibitor omeprazole.

OBJECTIVES: Proton pump inhibitors (PPIs) can limit the solubility of concomitant drugs, which can lead to decreased absorption and exposure. Reduced efficacy can be a consequence and in the case of an antimicrobial agent this may contribute to development of resistance. Patients chronically infected with the hepatitis C virus can be treated with a boceprevir-containing regimen and it is relevant to know if interactions between PPIs and boceprevir exist. This study was designed to investigate the influence of a frequently used PPI, omeprazole, on the pharmacokinetics of boceprevir and vice versa. METHODS: In this open-label, three-period, randomized, cross-over, Phase I study, healthy subjects were randomly assigned to 40 mg of omeprazole once daily for 5 days, 800 mg of boceprevir three times daily for 5 days and 40 mg of omeprazole once daily + 800 mg of boceprevir three times daily for 5 days, or the same treatment in a different order. Every treatment was followed by a wash-out period. At day 5 of every treatment pharmacokinetic blood sampling was performed for 8 h after medication intake. ClinicalTrials.gov: NCT01470690. RESULTS: All 24 subjects (15 males) completed the study and no serious adverse events were reported. Geometric mean ratios (90% CI) of the area under the plasma concentration-time curve up to 8 h (AUC0-8) and maximum plasma concentration (Cmax) of boceprevir with omeprazole versus boceprevir alone were 0.92 (0.87-0.97) and 0.94 (0.86-1.02), respectively. For omeprazole these values were 1.06 (0.90-1.25) for AUC0-8 and 1.03 (0.85-1.26) for Cmax for the combination versus omeprazole alone. CONCLUSIONS: Omeprazole did not have a clinically significant effect on boceprevir exposure, and boceprevir did not affect omeprazole exposure.

Lack of a clinically significant drug-drug interaction in healthy volunteers between the hepatitis C virus protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir.

BACKGROUND: Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are likely to use both HIV and HCV treatment. Drug-drug interactions have been demonstrated between boceprevir, an HCV protease inhibitor, and frequently prescribed antiretroviral drugs, such as efavirenz and boosted HIV protease inhibitors. Concomitant administration of boceprevir with these drugs should be avoided. This study was designed to investigate the absence of a drug-drug interaction between boceprevir and raltegravir, an HIV integrase inhibitor. METHODS: This was an open-label, randomized, 2-period, crossover phase 1 trial in 24 healthy volunteers. All subjects were randomly assigned to receive boceprevir 800 mg every 8 hours for 9 days plus a single dose of raltegravir 400 mg on day 10 followed by a washout period and a single dose of raltegravir 400 mg on day 38, or the same medication in reverse order. Blood samples for pharmacokinetics were collected and pharmacokinetic parameters were calculated. RESULTS: The geometric mean (GM) of raltegravir area under the concentration-time curve (AUC)(0-12h) and maximum plasma concentration (C(max)) for raltegravir + boceprevir vs raltegravir alone were 4.27 (95% confidence interval [CI], 3.22-5.66) vs 4.04 (95% CI, 3.09-5.28) mg * hour/L and 1.06 (95% CI, .76-1.49) vs 0.93 (95% CI, .70-1.23) mg/L, respectively. GM ratio estimates of raltegravir AUC(0-12h) and C(max) for raltegravir + boceprevir vs raltegravir alone were 1.04 (90% CI, .88-1.22) and 1.11 (90% CI, .91-1.36), respectively. The GM of boceprevir AUC(0-8h), C(max), and C(8h) were 5.45 (95% CI, 5.11-5.81) mg * hour/L, 1.88 (95% CI, 1.72-2.06) mg/L, and 0.09 (95% CI, .07-.11) mg/L, respectively. These data are comparable to those from historical controls. CONCLUSIONS: Due to the absence of a clinically significant drug interaction, raltegravir can be recommended for combined HIV/HCV treatment including boceprevir. CLINICAL TRIALS REGISTRATION: NCT01288417.

Rhabdomyolysis in an HIV-infected patient with impaired renal function concomitantly treated with rosuvastatin and lopinavir/ritonavir.

The authors describe an HIV-infected patient with moderate renal failure receiving combination antiretroviral therapy. Because of dyslipidaemia he was initially treated with pravastatin but developed rhabdomyolysis after a switch to rosuvastatin. With this case we illustrate that statins as well as antiretroviral therapy are susceptible to clinical relevant drug-drug or drug-disease interactions. Knowledge of these interactions is important to provide patients with the best possible care.