Sufficient Plasma Concentrations Research Articles

Consensus Statements on the Use of Novel Formulations of Isotretinoin: A Modified Delphi Process.

Oral isotretinoin remains a mainstay of treatment for severe, recalcitrant nodular acne. Novel formulations of isotretinoin have been developed over the past decade, including lidose isotretinoin and micronized isotretinoin. It is important to understand the differences between isotretinoin formulations to help guide clinical decision-making and selection of isotretinoin therapy. This study aims to provide evidence-based consensus statements regarding the use of novel formulations of isotretinoin for the treatment of moderate-to-severe acne. The Expert Consensus Group consisted of dermatologists with expertise in the treatment of acne. Voting members met in person to conduct a modified Delphi process; a maximum of 2 rounds of voting were conducted for each consensus statement. A total of 5 statements were generated regarding the use of novel formulations of isotretinoin, addressing the efficacy, tolerability, and side effects of novel isotretinoin formulations. All 5 statements achieved agreement with high consensus. The Expert Consensus Group agrees that individualized selection of isotretinoin therapy is important to maximize efficacy and minimize side effects. Compared to generic isotretinoin, micronized isotretinoin may require lower doses to achieve sufficient plasma concentrations. With the increased bioavailability of micronized formulation, there is no need to calculate cumulative dose; instead, the general recommendation with micronized isotretinoin is to treat for at least 5 months, or longer if needed to achieve clearance. Micronized isotretinoin can be taken in the fed or fasted state and has an acceptable safety profile. J Drugs Dermatol. 2024;23(6):429-432.     doi:10.36849/JDD.7971.

Non-therapeutic plasma levels in individuals utilizing curcumin supplements in daily life

IntroductionThe spice curcumin and its metabolites are widely used by cancer patients but have not shown proven health benefits in clinical studies, likely due to low plasma concentrations after oral intake. However, public interest in curcumin continues to grow, and companies claim enhanced absorption in their formulations. This study aims to determine if daily oral intake of curcumin leads to sufficient plasma concentrations for health effects. The study was registered in the Dutch Clinical Trial Register with ID NL5931.MethodsWe used a validated HPLC-MS/MS method to measure curcumin and its metabolites in 47 individuals using their own curcumin formulations. Questionnaires assessed other supplement and medication use. Plasma samples were collected before and 1.5 h after intake, analyzing curcumin and metabolite levels with and without β-glucuronidase pretreatment to measure conjugated and unconjugated forms.ResultsPlasma concentrations of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin, ranged between 1.0 and 18.6 ng/mL. Adding β-glucuronidase resulted in an increase of unconjugated curcumin plasma levels to 25.4 ng/mL; however still significantly below (1000-fold) a plasma concentration that is expected to have a beneficial health effect. The use of adjuvants like piperine did not result in higher curcumin plasma concentrations.DiscussionOur study shows that using oral curcumin supplements still does not result in therapeutic plasma levels. Health care practitioners need to be critical toward the claimed beneficial systemic health effects of current curcumin supplement use by their patients.Clinical Trial Registrationhttps://onderzoekmetmensen.nl/en/trial/25480, NL5931.

Impact of renal replacement therapy strategy on beta-lactam plasma concentrations: the BETAKIKI study—an ancillary study of a randomized controlled trial

BackgroundSepsis prognosis correlates with antibiotic adequacy at the early phase. This adequacy is dependent on antibacterial spectrum, bacterial resistance profile and antibiotic dosage. Optimal efficacy of beta-lactams mandates concentrations above the minimal inhibitory concentration (MIC) of the targeted bacteria for the longest time possible over the day. Septic acute kidney injury (AKI) is the most common AKI syndrome in ICU and often mandates renal replacement therapy (RRT) initiation. Both severe AKI and RRT may increase outside target antibiotic concentrations and ultimately alter patient’s prognosis.Patients and methodsThis is a secondary analysis of a randomized controlled trial that compared an early RRT initiation strategy with a delayed one in 620 critically ill patients undergoing severe AKI (defined by KDIGO 3). We compared beta-lactam trough concentrations between the two RRT initiation strategies. The primary outcome was the proportion of patients with sufficient trough plasma concentration of beta-lactams defined by trough concentration above 4 times the MIC. We hypothesized that early initiation of RRT could be associated with an insufficient antibiotic plasma trough concentration compared to patients allocated to the delayed strategy.ResultsOne hundred and twelve patients were included: 53 in the early group and 59 in the delayed group. Eighty-three patients (74%) had septic shock on inclusion. Trough beta-lactam plasma concentration was above 4 times the MIC breakpoint in 80.4% (n = 90) of patients of the whole population, without differences between the early and the delayed groups (79.2% vs. 81.4%, respectively, p = 0.78). On multivariate analysis, the presence of septic shock and a higher mean arterial pressure were significantly associated with a greater probability of adequate antibiotic trough concentration [OR 3.95 (1.14;13.64), p = 0.029 and OR 1.05 (1.01;1.10), p = 0.013, respectively). Evolution of procalcitonin level and catecholamine-free days as well as mortality did not differ whether beta-lactam trough concentration was above 4 times the MIC or not.ConclusionsIn this secondary analysis of a randomized controlled trial, renal replacement therapy initiation strategy did not significantly influence plasma trough concentrations of beta-lactams in ICU patients with severe AKI. Presence of septic shock on inclusion was the main variable associated with a sufficient beta-lactam concentration.Trial registration: The AKIKI trial was registered on ClinicalTrials.gov (Identifier: NCT01932190) before the inclusion of the first patient.

Biological Role of Folic Acid in Pregnancy and Possible Therapeutic Application for the Prevention of Preeclampsia.

The rationale and importance of folic acid supplementation during pregnancy for fetal congenital defect prevention are accepted worldwide. Moreover, a sufficient plasma concentration of folates can reduce the incidence of spontaneous abortions, and support the normal expansion of placental blood vessels, ensuring physiological placental blood flow, thus promoting appropriate fetal growth and development. Furthermore, there is emerging evidence that long-term supplementation with folic acid can effectively prevent preeclampsia. Preeclampsia is unique to the human species in complications during pregnancy, which contributes to maternal and perinatal mortality worldwide. In the pathogenesis of preeclampsia abnormal placental invasion, the excess of antiangiogenic factors and maternal-placental syndrome play a key role. Increased blood levels of homocysteine during pregnancy are associated with the risk of preeclampsia. Moreover, hyperhomocysteinemia has been proposed to be an independent risk factor for preeclampsia. Folate supplementation helps to decrease elevated levels of homocysteine; thus, the role of folic acid supplementation in pregnancy is even more important. Multiple reports suggest that folate administration decreases the level of serum homocysteine and, therefore, reduce the risk and severity of preeclampsia. However, the association between folic acid supplementation and the decreased risk of preeclampsia has been investigated with controversial conclusions. Currently, the optimal dose of folic acid that is effective for preeclampsia prevention remains uncertain. In this review, we aim to summarize the accumulated knowledge on the role of folic acid in the pathogenesis of preeclampsia, and the possible impact of folate supplementation on the decreased risk of preeclampsia.

Empagliflozin Reduces Renal Hyperfiltration in Response to Uninephrectomy, but Is Not Nephroprotective in UNx/DOCA/Salt Mouse Models.

Large-scale clinical outcome studies demonstrated the efficacy of SGLT2 inhibitors in patients with type II diabetes. Besides their therapeutic efficacy in diabetes, significant renoprotection was observed in non-diabetic patients with chronic kidney disease (CKD), suggesting the existence of glucose-independent beneficial effects of SGLT2 inhibitors. However, the relevant mechanisms by which SGLT2 inhibition delays the progression of renal injury are still largely unknown and speculative. Previous studies showed that SGLT2 inhibitors reduce diabetic hyperfiltration, which is likely a key element in renoprotection. In line with this hypothesis, this study aimed to investigate the nephroprotective effects of the SGLT2 inhibitor empagliflozin (EMPA) in different mouse models with non-diabetic hyperfiltration and progressing CKD to identify the underlying diabetes-independent cellular mechanisms. Non-diabetic hyperfiltration was induced by unilateral nephrectomy (UNx). Since UNx alone does not result in renal damage, renal disease models with varying degrees of glomerular damage and albuminuria were generated by combining UNx with high NaCl diets ± deoxycorticosterone acetate (DOCA) in different mouse strains with and without genetic predisposition for glomerular injury. Renal parameters (GFR, albuminuria, urine volume) were monitored for 4–6 weeks. Application of EMPA via the drinking water resulted in sufficient EMPA plasma concentration and caused glucosuria, diuresis and in some models renal hypertrophy. EMPA had no effect on GFR in untreated wildtype animals, but significantly reduced hyperfiltration after UNx by 36%. In contrast, EMPA did not reduce UNx induced hyperfiltration in any of our kidney disease models, regardless of their degree of glomerular damage caused by DOCA/salt treatment. Consistent with the lack of reduction in glomerular hyperfiltration, EMPA-treated animals developed albuminuria and renal fibrosis to a similar extent as H2O control animals. Taken together, the data clearly indicate that blockade of SGLT2 has the potential to reduce non-diabetic hyperfiltration in otherwise untreated mice. However, no effects on hyperfiltration or progression of renal injury were observed in hypervolemic kidney disease models, suggesting that high salt intake and extracellular volume might attenuate the protective effects of SGLT2 blockers.

Comparative Pharmacokinetics and Tissue Concentrations of Flunixin Meglumine and Meloxicam in Tilapia (Oreochromis spp.)

Evidence of pain perception in fish is well established, but analgesic use in aquaculture is limited. The objective was to investigate the comparative pharmacokinetics of flunixin administered intramuscularly (IM) and meloxicam administered IM or orally (PO) in tilapia. Two hundred and seventy fish were assigned to 1 of 3 treatment groups: flunixin meglumine IM (2.2 mg/kg); meloxicam IM (1 mg/kg); or meloxicam PO (1 mg/kg). Blood and tissue samples were collected from 6 fish per treatment at 14 time points for 10 days. Drug concentrations were determined using ultra-high-pressure liquid chromatography coupled with mass spectroscopy. Plasma concentration versus time data were analyzed with a non-compartmental approach using a commercially available software. Flunixin reached a mean maximum concentration (Cmax) of 4826.7 ng/mL at 0.5 h, had a terminal half-life (T1/2) of 7.34 h, and an area under the concentration–time curve extrapolated to infinity (AUCINF_obs) of 25,261.62 h·ng/mL. Meloxicam IM had a T1/2 of 9.4 h after reaching a Cmax of 11.3 ng/mL at 2 h, with an AUCINF_obs of 150.31 h·ng/mL. Meloxicam PO had a T1/2 of 1.9 h after reaching a Cmax of 72.2 ng/mL at 2 h, with an AUCINF_obs of 400.83 h·ng/mL. Tissue concentrations of both drugs were undetectable by 9 h. Flunixin reached a sufficient plasma concentration to potentially have an analgesic effect, while meloxicam, when administered at the given dosage, likely would not.

Optimal loading dose of meropenem before continuous infusion in critically ill patients: a simulation study

The aim of this study was to investigate optimal loading doses prior to continuous infusion of meropenem in critically ill patients. A previously published and successfully evaluated pharmacokinetic model of critically ill patients was used for stochastic simulations of virtual patients. Maintenance doses administered as continuous infusion of 1.5–6 g/24 h with preceding loading doses (administered as 30 min infusion) of 0.15–2 g were investigated. In addition to the examination of the influence of individual covariates, a best-case and worst-case scenario were simulated. Dosing regimens were considered adequate if the 5th percentile of the concentration–time profile did not drop at any time below four times the S/I breakpoint (= 2 mg/L) of Pseudomonas aeruginosa according to the EUCAST definition. Low albumin concentrations, high body weight and high creatinine clearances increased the required loading dose. A maximum loading dose of 0.33 g resulted in sufficient plasma concentrations when only one covariate showed extreme values. If all three covariates showed extreme values (= worst-case scenario), a loading dose of 0.5 g was necessary. Higher loading doses did not lead to further improvements of target attainment. We recommend the administration of a loading dose of 0.5 g meropenem over 30 min immediately followed by continuous infusion.

180 Comparative Pharmacokinetics of Flunixin Meglumine and Meloxicam in Tilapia (Oreochromis Spp.)

Abstract Aquaculture is one of the largest growing sectors of the world food supply. There is evidence of pain perception in fish, but analgesic use in aquaculture is limited, as little information is available on the properties of analgesic drugs in fish. The objective was to investigate the comparative pharmacokinetics of flunixin administered intramuscularly and meloxicam administered intramuscularly or orally in tilapia. Two hundred-seventy fish were enrolled and assigned to 1 of 3 treatment groups 1) flunixin meglumine administered intramuscularly at a dose of 2.2 mg/kg; 2) meloxicam administered intramuscularly at a dose of 1 mg/kg; or 3) meloxicam administered orally at a dose of 1 mg/kg. Blood samples were collected from 6 fish per treatment group at 14 timepoints out to 10 days post-drug administration. Plasma drug concentrations were determined using ultra-high pressure liquid chromatography coupled with mass spectroscopy. The mean and standard error of the plasma concentration were calculated for each treatment at each timepoint. The plasma concentration versus time data were analyzed with a non-compartmental approach using a commercially available software (Phoenix®, Version 8.3, Certara, Inc., Princeton, NJ, USA). Flunixin reached a mean maximum concentration (Cmax) of 4826.7 ng/mL at 0.5 h, had a terminal half-life (T1/2) of 0.5h, and an area under the concentration time curve extrapolated to infinity (AUCINF_obs) of 25,261.62 h*ng/mL. Intramuscular meloxicam had a T1/2 of 9.4 h after reaching a Cmax of 11.3 ng/mL at 2 h, with an AUCINF_obs of 150.31 h*ng/mL. Oral meloxicam has a T1/2 of 1.9 h after reaching a Cmax of 72.2 ng/mL at 2 h, with an AUCINF_obs of 400.83 h*ng/mL. In conclusion, flunixin, when administered intramuscularly, reaches sufficient plasma concentrations to potentially have an effect, while meloxicam when administered intramuscularly or orally at the given dosage likely does not due to the relatively low plasma concentration.

Comparative Study of Different Products of Carbamazepine Tablets Available in Iraqi Market

Carbamazepine (CBZ) is a widely used antiepileptic drug to control grand mal epilepsy, as well as for the treatment of peripheral neuralgia. According to the biopharmaceutical classification system (BCS), CBZ is considered a class II drug. CBZ is characterized by a slow and irregular gastrointestinal absorption, with irregular oral bioavailability; due to its low water solubility. Therefore, the release of the drug from the dosage form (tablets in this study) and the subsequent step of dissolution represent the most important parameters that decide whether a sufficient plasma concentration will be achieved or not. In the current study, the FTIR study for the pure API, CBZ, and the different commercially available brands of CBZ conventional tablets, available in the Iraqi drug market (Mosul city as an example), were examined. Subsequently, various quality control parameters such as the weight variation, content uniformity, friability, and hardness of the conventional CBZ tablets were conducted. Moreover, the disintegration and the dissolution tests of the different brands of CBZ available in the Iraqi drug market were performed.
 Keywords: Antiepileptic Drug, Bioequivalence; Epilepsy; Generic; Brand vs generic; IVIVC; QC

Pharmacokinetics and Efficacy of a Long-lasting, Highly Concentrated Buprenorphine Solution in Mice.

Buprenorphine is a commonly used opioid for mitigating pain in laboratory mice after surgical procedures; however, the dosing interval necessary for standard buprenorphine may require treatment every 4 to 6 h to maintain an adequate plane of analgesia. An alternative formulation that provides prolonged plasma concentration with long-lasting effects would be beneficial in achieving steady-state analgesia. We evaluated a long-lasting and highly concentrated formulation of buprenorphine (Bup-LHC) in mice. Pharmacokinetic analysis was performed to assess plasma concentrations in male C57BL/6J (B6) and female CD1 mice after subcutaneous injection of 0.9 mg/kg. The Bup-LHC formulation provided plasma drug levels that exceeded the therapeutic level for at least 12 h in male B6 mice and was below therapeutic levels by 8 h in female CD1 mice. An experimental laparotomy model was used to assess analgesic efficacy. Female CD1 mice were treated with either Bup-LHC (0.9 mg/kg) or saline at 1 h before undergoing an ovariectomy via a ventral laparotomy. At 3, 6, 12, 24, and 48 h after surgery, pain was assessed based on the following behaviors: orbital tightness, grooming, wound licking, rearing, arched posture, ataxia, piloerection, nest building, and general activity. At 3 and 6 h after surgery, Bup-LHC-treated mice had significantly less wound licking and orbital tightness and considerably higher activity levels than did saline-treated mice. At 12 h, wound licking, orbital tightness and activity in Bup-LHC-treated mice were no longer significantly different from those of saline-treated mice. The results of this study suggest that Bup-LHC at 0.9 mg/kg provides sufficient plasma concentrations for analgesia in mice for 6 to 12 h after administration, as demonstrated behaviorally for at least 6 h after surgery.

Sunscreen Safety: a Review of Recent Studies on Humans and the Environment

To provide an up-to-date synopsis of the literature on the safety of sunscreen active ingredients in humans and the environment and highlight regulatory changes in the USA. Currently, as per the US Food and Drug Administration, the only ultraviolet filters generally recognized as safe and effective are inorganic zinc oxide (ZnO) and titanium dioxide (TiO2). In vivo human systemic absorption studies found that common organic filters attain sufficient plasma concentrations to require carcinogenicity and reproductive studies. In vivo human skin penetration studies showed ZnO nanoparticles (ZnO-NP) did not penetrate the stratum corneum. Limited quantities of TiO2-NP may be absorbed systemically. In laboratory settings, corals exposed to oxybenzone manifested concentration-dependent toxicity and bleaching. In response, bills passed in Hawaii and elsewhere ban sales of oxybenzone-containing sunscreens. ZnO-NP, but not TiO2-NP, caused coral bleaching under controlled conditions. The collective knowledge on sunscreen safety is continually evolving, with many preliminary findings. Studies on the effects of systemic absorption of organic filters in humans are forthcoming; importantly, there has been no evidence of harm over decades of use. Organic (less so inorganic) filters caused coral bleaching in controlled environments, but filter concentrations may not have been realistic, and bleaching is predominantly driven by other factors. No present evidence suggests any marketed sunscreens should be avoided. For consumers with concerns, inorganic ZnO and TiO2 are supported by the most reassuring data at the time of writing.

Phase I/IIa, open-label, multicentre study to evaluate the optimal dosing and safety of ODM-203 in patients with advanced or metastatic solid tumours

BackgroundGenetic alterations in fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor receptor (VEGFR) signalling are observed in various tumours. We report a first-in-human phase I/IIa trial evaluating tolerability, pharmacokinetics and preliminary antitumour activity of ODM-203, a novel FGFR and VEGFR inhibitor.MethodsOpen-label, non-randomised, multicentre, phase I/IIa dose escalation and expansion study in patients with advanced or metastatic solid tumours.ResultsOverall, 84 patients received treatment; optimal tablet dose was found to be 400 mg/day with food. All patients experienced at least one adverse event; the majority (89.2%) were grade 1 or 2% and 70.4% were considered treatment related. The most commonly reported events were bilirubin increase-related events (75%) and diarrhoea (50%).Overall response rate was 9.2% and median progression-free survival was 16.1 and 12.4 weeks for patients with aberrant or non-aberrant FGFR tumours. Median time on treatment was 10.1 weeks for all patients and 14.5 weeks for patients who received 400 mg tablets.ConclusionThis study suggests ODM-203 400 mg/day results in sufficient plasma concentrations and acceptable tolerability in most patients. Preliminary signs of therapeutic activity of ODM-203 in patients with solid tumours was observed.Trial registration numberNCT02264418.

Effects of Milk or Apple Juice Ingestion on the Pharmacokinetics of Elvitegravir and Cobicistat in Healthy Japanese Male Volunteers: A Randomized, Single-Dose, Three-Way Crossover Study.

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/FTC/TAF) is specified in its package insert to be taken with food to obtain sufficient exposure of EVG. It has been reported that a nutritional protein-rich drink shows comparable pharmacokinetics (PK) of EVG to those with a standard breakfast. In this study, the PK profiles of EVG and COBI were evaluated by administration of a single dose of EVG/COBI/FTC/TAF, after ingestion of either a nutritional protein-rich drink, milk, or apple juice. The geometric means for Cmax and AUCinf of EVG following milk ingestion slightly decreased by 21% and 14%, respectively, and those following apple juice ingestion decreased by 67% and 61%, respectively, compared with a nutritional protein-rich drink. There were no differences in any PK parameters of COBI. Therefore, taking EVG/COBI/FTC/TAF after milk or apple juice ingestion appeared to be not appropriate. However, for plasma trough concentrations (Ctau ), it is known that Ctau is best correlated with the efficacy of EVG. The mean C24 of EVG after milk ingestion was 620.6 ng/mL, which was more than 10-fold the protein binding-adjusted 95% inhibitory concentration. With all the above considerations, it was concluded that taking EVG/COBI/FTC/TAF with milk could be an option to maintain sufficient plasma concentrations of EVG.

Lead Optimization Generates CYP11B1 Inhibitors of Pyridylmethyl Isoxazole Type with Improved Pharmacological Profile for the Treatment of Cushing's Disease.

Cushing's disease, characterized by elevated plasma cortisol levels, can be controlled by inhibition of 11β-hydroxylase (CYP11B1). The previously identified selective and potent CYP11B1 inhibitor 5-((5-methylpyridin-3-yl)methyl)-2-phenylpyridine Ref 7 (IC50= 2 nM) exhibited promutagenic potential as well as very low oral bioavailability in rats (F = 2%) and was therefore modified to overcome these drawbacks. Successful lead optimization resulted in similarly potent and selective 5-((5-methoxypyridin-3-yl)methyl)-3-phenylisoxazole 25 (IC50 = 2 nM, 14-fold selectivity over CYP11B2), exhibiting a superior pharmacological profile with no mutagenic potential. Furthermore, compound 25 inhibited rat CYP11B1 (IC50 = 2 μM) and showed a high oral bioavailability (F = 50%) and sufficient plasma concentrations in rats, providing an excellent starting point for a proof-of-principle study.

The “induced hyperactivity” test for the de-risking of potential off-target activity of antihypertensive drugs

IntroductionCompound X is a new proprietary antihypertensive agent that induces its pharmacodynamic effect at an approximate plasma Cmax.u of 0.6nmol/L (rat hypertension model). However, Compound X also shows potent off-target activity at PDE-10a (IC50~12nmol/L). Since PDE-10a is expressed predominantly in brain (striatum) and inhibition/knockout of PDE-10a have been reported to result in anti-psychotic effects, we have established the “induced hyperactivity” test for CNS de-risking of Compound X. MethodsMale Wistar rats treated orally with vehicle or Compound X (single dose; 1–3–10mg/kg) were assessed for exploratory locomotor activity following induction of hyperactivity by d-amphetamine (2mg/kg) or the NMDA antagonist MK-801 (0.2mg/kg). The assay was validated with anti-psychotic drugs (haloperidol, clozapine). ResultsInduced hyperactivity was not antagonized by Compound X at doses relevant for its primary pharmacodynamic activity (0.1–0.3mg/kg, rat). Although sufficient plasma concentrations were reached with Compound X (Cmax.u up to ~8nmol/L at 10mg/kg) to show its PDE-10a activity, its low brain penetration (~10%) likely precluded any meaningful PDE-10a inhibition. In comparison, other blood pressure lowering agents such as prazosin (alpha-1 adrenoceptor antagonist) and isradipine (L-Type Ca2+ channel blocker), but not the NO-donor ISDN, tended to attenuate induced hyperactivity in rats at high doses. ConclusionThe relevance of a potent in-vitro off-target hit (PDE-10a inhibition) by Compound X was attenuated by a robust in-vivo assay (rat induced hyperactivity test), hence lowering the potential liability profile of Compound X. Finally, this piece of investigative safety pharmacology work enabled early de-risking of Compound X based on its primary pharmacodynamic activity in a relevant rat model.

Abstract P5-14-05: Phase 1 evaluation of the androgen receptor modulator CR1447 in patients with advanced breast cancer (SAKK 21/12)

Abstract Background: CR1447 (4-OH-testosterone, 4-OHT), a steroidal small molecule, strongly binds to the androgen receptor (AR) and has aromatase inhibiting activity. Pre-clinical studies show that CR1447 given as an ointment is efficiently absorbed and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells. Methods: CR1447 was administered topically on a daily basis to patients with ER-positive/HER2-negative or ER-negative/PR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. One cycle was defined as 21 days of treatment. Disease evaluation was performed at 3 and 6 months in order to determine tumor response (i.e. complete/partial remission and stable disease) in 3 cohorts of 3 evaluable patients each plus 3 confirmatory patients (dose escalation 100, 200, 400 mg). Results: 14 patients have been treated for a total of 38 cycles. Two patients are still on treatment at the time of analysis. Two patients, one in cohort 1 and one in cohort 2, showed early tumor progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447, resulting in sufficient plasma concentrations of 4-OHT. 4-OH-androstenedione, a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Conclusions: CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative and ER-negative/PR-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day. Citation Format: Schoenfeld W, Zweifel M, Thuerlimann B, Riniker S, Weder P, von Moos R, Pagani O, Bigler M, Rothgiesser KM, Pilop C, Brauchli P, Tapia C, Sessa C. Phase 1 evaluation of the androgen receptor modulator CR1447 in patients with advanced breast cancer (SAKK 21/12). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-05.

Potential clinical benefit of therapeutic drug monitoring of imatinib in oncology

Imatinib mesylate is a competitive inhibitor of BCR/ ABL tyrosine kinase and inhibits also several receptor tyrosin kinases. Since its launch to the market, imatinib has proven to be very valuable in the treatment of Philadelphia chromosome (BCR/ ABL) - positive (Ph+) chronic myeloid leukemia and Kit (CD117) positive gastrointestinal stromal tumors. The drug is metabolized by cytochrome P450, and there are many clinically important pharmacokinetic drug-drug interactions described in the literature. Frequent polypharmacy in oncological patients increases probability of such interactions, and also adherence may play its role during longterm treatment. Fixed dosing therapeutic regimens fail to respect known interindividual variability in pharmacokinetics of the drug and thus, some patients may not achieve sufficient plasma concentrations. Based on current evidence, there seems to be a relationship between plasma concentration and clinical response to imatinib. Therefore, imatinib appears to be suitable candidate for therapeutic drug monitoring. Here, we present an overview of pharmacokinetics, drug-drug interactions and current knowledge and suggestions on therapeutic drug monitor-ing of imatinib, its potential benefits and limitations.

Discovery and Exploitation of Novel Targets by Approved Drugs

Discovery and Exploitation of Novel Targets by Approved Drugs

Plasma disposition of enrofloxacin following intravenous and intramuscular administration in donkeys

This study was designed to investigate the plasma disposition and systemic availability of enrofloxacin (ENR) following intramuscular and intravenous administrations. Six donkeys (Equus asinus) were used in this study. The...

Formulation development and statistical optimization of chronotherapeutic tablets of indometacin

Chronotherapeutic drug delivery offers a new approach in the pharmacologic interventions design for the effective treatment in the diseases which follows circadian rhythm. In the present study chronotherapeutic tablets of indometacin was designed to match the timing of rheumatoid arthritis treatment with the intrinsic illness timing. The developed chronotherapeutic delivery system consists of a core tablet containing the active ingredient along with osmogents and other excipients, which was coated with a swellable polymer, hydroxyl propyl methyl cellulose by compression coating technique. The time controlled release was achieved by coating the entire system with a combination of pH-independent polymer, Eudragit RS 100 and Eudragit RL 100 (1:1). The optimization technique using Box–Behnken design was employed for the selection of the ideal formula. The optimization procedure was validated, and the observed value of the ideal batch was found to be similar with the predicted values within 5% of predicted error. The formulation when administered at bed time starts releasing the drug after a lag time of 4 h and provides sufficient plasma concentration after 6 h of normal sleep. Thus, the tablets can be successfully used for the chronotherapeutic drug delivery of indometacin in the treatment of rheumatoid arthritis.