Impact of patient education on plasma concentrations and effectiveness of posaconazole oral suspension under clinical conditions.

Posaconazole prophylaxis is recommended for patients with acute myeloid leukaemia during induction chemotherapy. Although a tablet formulation with better oral bioavailability is available, some patients have to rely on the oral suspension in clinical routine. Therefore, effectiveness of posaconazole oral suspension under real-life clinical conditions and impact of patient education about the correct intake on its plasma concentrations were assessed in this study. Altogether 96 patients receiving 160 cycles of induction chemotherapy were retrospectively (40 patients) and prospectively (56 patients) analysed. Patients were assigned into two groups for each chemotherapy cycle according to the application of antifungal prophylaxis (A: posaconazole oral suspension, 200 mg three times a day ≥7 days; B: intake <7 days, fluconazole or no prophylaxis). Antifungal prophylaxis and therapy were analysed for each cycle. Additionally, plasma concentrations were determined from prospectively included subjects of group A who were intensively educated to perform a correct drug intake. Systemic antifungal therapy was statistically started less often in group A (26% vs 53%; P = 0.002). Posaconazole prophylaxis was associated with a lower risk of proven invasive fungal infection (P = 0.003). Median plasma concentration apparently increased between the first and second time of determination effected by an initial intensive on-site patient education. The clinical effectiveness of posaconazole oral suspension was confirmed. A detailed patient education at the beginning of the treatment with posaconazole oral suspensions seems to be of primary importance for efficient plasma concentrations.

Pregnancy-Associated Changes in Pharmacokinetics: A Systematic Review.

BACKGROUND: Women are commonly prescribed a variety of medications during pregnancy. As most organ systems are affected by the substantial anatomical and physiological changes that occur during pregnancy, it is expected that pharmacokinetics (PK) (absorption, distribution, metabolism, and excretion of drugs) would also be affected in ways that may necessitate changes in dosing schedules. The objective of this study was to systematically identify existing clinically relevant evidence on PK changes during pregnancy. METHODS AND FINDINGS: Systematic searches were conducted in MEDLINE (Ovid), Embase (Ovid), Cochrane Central Register of Controlled Trials (Ovid), and Web of Science (Thomson Reuters), from database inception to August 31, 2015. An update of the search from September 1, 2015, to May 20, 2016, was performed, and relevant data were added to the present review. No language or date restrictions were applied. All publications of clinical PK studies involving a group of pregnant women with a comparison to nonpregnant participants or nonpregnant population data were eligible to be included in this review. A total of 198 studies involving 121 different medications fulfilled the inclusion criteria. In these studies, commonly investigated drug classes included antiretrovirals (54 studies), antiepileptic drugs (27 studies), antibiotics (23 studies), antimalarial drugs (22 studies), and cardiovascular drugs (17 studies). Overall, pregnancy-associated changes in PK parameters were often observed as consistent findings among many studies, particularly enhanced drug elimination and decreased exposure to total drugs (bound and unbound to plasma proteins) at a given dose. However, associated alterations in clinical responses and outcomes, or lack thereof, remain largely unknown. CONCLUSION: This systematic review of pregnancy-associated PK changes identifies a significant gap between the accumulating knowledge of PK changes in pregnant women and our understanding of their clinical impact for both mother and fetus. It is essential for clinicians to be aware of these unique pregnancy-related changes in PK, and to critically examine their clinical implications.

Treatment with rilpivirine does not alter plasma concentrations of the CYP3A substrates tadalafil and midazolam in humans.

OBJECTIVES: Antiretroviral combination therapy of patients infected with HIV has greatly increased their life expectancy. Hence, the treatment of HIV-related long-term complications and age-related comorbidities has become more important. Reported incidence rates of erectile dysfunction (ED) and pulmonary arterial hypertension (PAH) are increasing in HIV-positive patients, potentially requiring treatment with phosphodiesterase 5 inhibitors such as sildenafil or tadalafil. In vitro, the NNRTI rilpivirine is both a pregnane X receptor agonist and cytochrome P450 (CYP) 3A inhibitor. Clinical data concerning the potential effects of rilpivirine coadministration on the pharmacokinetics of the CYP3A substrate tadalafil are lacking. METHODS: We enrolled 20 healthy volunteers in an open-label, two-part, one-arm Phase I clinical trial to investigate acute and chronic effects of multiple doses of 25 mg of oral rilpivirine on single-dose and steady-state pharmacokinetics of multiple oral 20 mg doses of tadalafil. CYP3A activity was measured simultaneously with the oral midazolam microdose test. RESULTS: We did not observe a change of tadalafil single-dose and steady-state exposure or of CYP3A activity measured at initiation, during maintenance and upon discontinuation of rilpivirine treatment after single-dose and chronic administration of rilpivirine. CONCLUSIONS: Tadalafil can be combined with rilpivirine without dose adjustment or drug monitoring in HIV patients with ED or PAH. Rilpivirine at daily therapeutic doses of 25 mg does not induce or inhibit CYP3A-dependent drug metabolism.

First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B.

BACKGROUND & AIMS: Myrcludex B is a first-in-class compound, which blocks entry of hepatitis B and D virus into hepatocytes in vitro and in animal models. Based on the required preclinical data we aimed to translate this compound into the first application in humans. METHODS: Single ascending doses of myrcludex B, a 47 amino acid peptide, were administered up to 20mg intravenously and 10mg subcutaneously in a prospective open first-in-human, phase I clinical trial to 36 healthy volunteers. Safety, tolerability and plasma concentrations of myrcludex B were assessed and a pharmacokinetic model was derived. RESULTS: Myrcludex B was well tolerated and no serious or relevant AEs representing off-target effects, and no immunogenic effects were observed up to the highest applied dose of 20mg (intravenously). Myrcludex B showed dose-dependent pharmacokinetics, best described by a 2-compartment target-mediated drug disposition model. Bioavailability of the subcutaneous application was large (85%). Interindividual variability was moderate. The pharmacokinetic model suggested that subcutaneous doses of 10mg and above reach a target saturation of over 80% for at least 15h. CONCLUSIONS: Myrcludex B showed excellent tolerability up to high doses. Pharmacologic properties followed a 2-compartment target-mediated drug disposition model. These findings are vital for planning of further multiple dose efficacy trials in patients. LAY SUMMARY: After showing antiviral activity in cell culture and animal models, myrcludex B, a new drug intended for the treatment of hepatitis B and D, has been administered the first time in humans. Healthy volunteers received the drug intravenously and subcutaneously up to high doses (20mg). The drug was well tolerated and the characteristics of the drug determining its way in the human body could be described. These results will allow testing myrcludex B in hepatitis B and D patients.

Dose-Dependent Bioavailability and CYP3A Inhibition Contribute to Non-Linear Pharmacokinetics of Voriconazole.

Voriconazole is both a substrate and a potent inhibitor of cytochrome P450 (CYP) 3A. It has a high bioavailability and non-linear pharmacokinetics. We investigated the pharmacokinetics and metabolism of 50 mg and 400 mg doses of intravenous and oral voriconazole in 14 healthy volunteers. Concurrently, we determined systemic and presystemic CYP3A activity with microdosed midazolam. Bioavailability of voriconazole 50 mg was 39 % compared with 86 % of the 400 mg dose. Voriconazole area under the concentration-time curve extrapolated to infinity (AUC∞) was 416 and 16,700 h·ng/mL for the 50 and 400 mg oral doses, respectively, and 1110 and 19,760 h·ng/mL for the 50 and 400 mg intravenous doses, respectively. Midazolam metabolism was dose-dependently inhibited by voriconazole. Dose-dependent autoinhibition of CYP3A-dependent first-pass metabolism and systemic metabolism is a possible explanation for the dose-dependent bioavailability and elimination of voriconazole, either as additional mechanism to, or instead of, saturation of presystemic metabolism. Higher bioavailability and non-linear pharmacokinetics are expected to be a common property of drugs that are substrates and inhibitors of CYP3A, e.g. clarithromycin.

Percutaneous instillation of physiological saline solution for the treatment of femoral pseudoaneuryms.

OBJECTIVE: To investigate the efficacy of para-aneurysmal saline injection for closure of postcatheterization pseudo-aneurysm (PA) at the vascular access site. METHODS: Fifty-one consecutive patients with postcatheterization PA at the vascular access site were included to undergo percutaneous para-aneurysmal saline injection. In case of technical failure the day after, PA were treated by bovine thrombin injection. Anatomical properties of the PA were recorded as were details to injection. RESULTS: Initially all patients exhibited success which was reduced to 43 % at day one. A saline volume of median 7 ml (interquartile range 6-8 ml) has been injected. The amount of injected saline was not different in patients with and without treatment success at day one (P = 0.6). Several anatomical properties of the PA exhibited marked differences in patients with or without success. The length (10.3 mm (7.8-12.0) vs. 12.5 mm (10.3-15.0); P = 0.009) and the angulation (110° (100-118) vs. 140° (129-146); P < 0.001) of the fistula/vessel axis was statistically different between groups. The peak systolic velocity failed to show significance with a tendency to higher values in the ineffective study group (P = 0.07). No peripheral complications occurred. CONCLUSION: Para-aneurysmal saline injection may be a therapeutic alternative to percutaneous thrombin injection in patients exhibiting favorable anatomical properties.

St. John's wort treatment in women bears risks beyond pharmacokinetic drug interactions.

We analyzed adverse events in a clinical phase I trial to assess dose-dependent metabolic effects of St. John's wort co-administered with rifampicin in 12 healthy volunteers. Within 3-6 days after increasing the St. John's wort dose from 300 to 600 mg TID, five of six female participants developed ambient temperature-dependent allodynia and paresthesia in sun-exposed areas (back of the hands and perioral and nasal area). Aggravation of symptoms resulted in persistence of paresthesia and phototoxic erythrodermia. None of the male participants showed any of these effects. Gender, duration of treatment, dose, and solar exposure seem to be extrinsic and host factors facilitating St. John's wort-induced neuropathy. The risk to develop this adverse effect is almost exclusively present in women.

Midazolam microdose to determine systemic and pre-systemic metabolic CYP3A activity in humans.

AIM: We aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam. METHODS: In an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics. RESULTS: Dose-normalized AUC and Cmax were 37.1 ng ml(-1 ) h [95% CI 35.5, 40.6] and 39.1 ng ml(-1) [95% CI 30.4, 50.2] for the microdose and 39.0 ng ml(-1 ) h [95% CI 36.1, 42.1] and 37.1 ng ml(-1) [95% CI 26.9, 51.3] for the milligram dose. CLmet was 253 ml min(-1) [95% CI 201, 318] vs. 278 ml min(-1) [95% CI 248, 311] for intravenous doses and 1880 ml min(-1) [95% CI 1590, 2230] vs. 2050 ml min(-1) [95% CI 1720, 2450] for oral doses. Oral bioavailability of a midazolam microdose was 23.4% [95% CI 20.0, 27.3] vs. 20.9% [95% CI 17.1, 25.5] after the regular dose. Hepatic and gut extraction ratios for microgram doses were 0.44 [95% CI 0.39, 0.49] and 0.53 [95% CI 0.45, 0.63] and compared well with those for milligram doses (0.43 [95% CI 0.37, 0.49] and 0.61 [95% CI 0.53, 0.70]). CONCLUSION: The pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to assess safely systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity.

Systemic exposure of topical erythromycin in comparison to oral administration and the effect on cytochrome P450 3A4 activity.

AIMS: Erythromycin is a macrolide antibiotic, which is frequently used as a topical formulation for the treatment of acne. It is also known as an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A4. In this study, the systemic availability of topical erythromycin, hence the influence on the activity of CYP3A, is evaluated in comparison to orally administered erythromycin. METHODS: Sixteen healthy volunteers received consecutively topical (two applications of 800 mg) and oral erythromycin (two dose groups, 250 and 1000 mg, with n = 8) to assess erythromycin pharmacokinetics. A microdose of midazolam (3 µg orally) was used to determine the effect on CYP3A activity. RESULTS: After topical administration, erythromycin was detected in the plasma of every participant without causing a statistically significant alteration of CYP3A activity. After oral administration, the dose-normalized erythromycin exposure (AUC∞ ) was 1335 h ng ml(-1) after 250 mg and 3-fold higher after the 1000 mg dose (4051 h ng ml(-1); P < 0.01), suggesting nonlinear pharmacokinetics of erythromycin. Both oral doses inhibited CYP3A activity; midazolam clearance was decreased to 61% (250 mg) and 21% (1000 mg). The relationship between erythromycin exposure and CYP3A activity (Hill equation) revealed a 50% reduction of CYP3A activity by an erythromycin AUC∞ of 2106 h ng ml(-1). CONCLUSIONS: Topical erythromycin did not cause clinically relevant CYP3A alterations, although low systemic availability of erythromycin was observed. This supports the assumption that treatment with topical erythromycin is not critical in terms of CYP3A inhibition. Furthermore, substantial nonlinearity of erythromycin pharmacokinetics after two different oral doses was observed, possibly due to autoinhibition.

Substantially increased sildenafil bioavailability after sublingual administration in children with congenital heart disease: two case reports.

INTRODUCTION: Pulmonary hypertension is a progressive disease of diverse origin with devastating consequences in adults as well as in children. The phosphodiesterase 5 inhibitor sildenafil successfully lowers pulmonary vascular resistance. However, because of its poor enteral absorption, resulting in ineffective plasma concentrations, responses in infants and children are often erratic. CASE PRESENTATIONS: We report the cases of two Caucasian boys, one born at term (case 1) and one aged 2.5 years (case 2), who had structural cardiac and pulmonary defects accompanied by symptomatic pulmonary hypertension. They received sildenafil enterally and sublingually and also intravenously in one of them. Plasma samples were taken at various time points to determine the plasma concentrations of sildenafil and its partially active metabolite. Sildenafil and N-desmethyl sildenafil were quantified using a validated liquid chromatography/mass spectrometry method. Oxygen partial pressure was determined from routine arterial blood gas samples. CONCLUSION: In agreement with previous observations in adults, we found that sublingual sildenafil was more extensively absorbed in our two pediatric patients. After sublingual administration, sildenafil plasma concentrations increased by 314% to 361% compared to enteral dosing. Concurrently, the metabolic ratio increased, suggesting not only that the overall absorption was enhanced but also that first-pass metabolism was partially bypassed. In case 2, the free fraction of sildenafil was 0.9%, which is considerably less than in adults (4%), suggesting that, in case 2, higher plasma concentration would have been needed to achieve effects similar to those in adults. Sublingual sildenafil appears to be a promising alternative route of administration in children with poor enteral absorption.

Drug interactions with phytotherapeutics in oncology.

INTRODUCTION: Because 30 to 70% of tumour patients use complementary and alternative medicines; herb-drug combinations are particularly frequent in this population. Some of these combinations can critically alter exposure of anti-neoplastic and palliative treatment. AREAS COVERED: This review summarises pharmacokinetic drug interactions caused by the herbal products most frequently used by tumour patients (garlic, ginkgo, ginseng, echinacea and St John's wort [SJW]). EXPERT OPINION: Herb-drug interactions, in general, and some interactions in particular (e.g., transporters, Phase II metabolism enzymes) are still poorly investigated and are difficult to evaluate because mixtures are administered with variable and often unspecified amounts of ingredients. Current evidence suggests that garlic and ginkgo can be safely co-administered, whereas CYP2C9 substrates (e.g., warfarin) should be monitored closely when ginseng therapy is started. Echinacea can induce drug metabolism mediated by CYP3A, but most likely relevant when administered with substances with a narrow therapeutic index or low oral bioavailability. The most relevant herbal perpetrator drug is SJW, which has substantial impact on CYP3A4- and CYP2C9-mediated metabolism and P-glycoprotein-mediated transport. This may lower exposure of co-administered drugs by up to 70%. Such an interaction is expected to occur with most of the tyrosine kinase inhibitors, but current evidence is limited.