Safety, Pharmacokinetics, and Causal Prophylactic Efficacy of KAF156 in a Plasmodium falciparum Human Infection Study.

BACKGROUND: KAF156 is a novel antimalarial drug that is active against both liver- and blood-stage Plasmodium parasites, including drug-resistant strains. Here, we investigated the causal prophylactic efficacy of KAF156 in a controlled human malaria infection (CHMI) model. METHODS: In part 1, healthy, malaria-naive participants received 800 mg KAF156 or placebo 3 hours before CHMI with P. falciparum-infected mosquitoes. In part 2, KAF156 was administered as single doses of 800, 300, 100, 50, or 20 mg 21 hours post-CHMI. All participants received atovaquone/proguanil treatment if blood-stage infection was detected or on day 29. For each cohort, 7-14 subjects were enrolled to KAF156 treatment and up to 4 subjects to placebo. RESULTS: KAF156 at all dose levels was safe and well tolerated. Two serious adverse events were reported-both resolved without sequelae and neither was considered related to KAF156. In part 1, all participants treated with KAF156 and none of those randomized to placebo were protected against malaria infection. In part 2, all participants treated with placebo or 20 mg KAF156 developed malaria infection. In contrast, 50 mg KAF156 protected 3 of 14 participants from infection, and doses of 800, 300, and 100 mg KAF156 protected all subjects against infection. An exposure-response analysis suggested that a 24-hour postdose concentration of KAF156 of 21.5 ng/mL (90% confidence interval, 17.66-25.32 ng/mL) would ensure a 95% chance of protection from malaria parasite infection. CONCLUSIONS: KAF156 was safe and well tolerated and demonstrated high levels of pre- and post-CHMI protective efficacy. CLINICAL TRIALS REGISTRATION: NCT04072302.

Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa.

BACKGROUND: The novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether-lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa. METHODS: This was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether-lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial. RESULTS: Overall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether-lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether-lumefantrine. Cipargamin was well tolerated with no safety concerns. CONCLUSIONS: This active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin. Trial registration ClinicalTrials.gov number: NCT03334747 (7 Nov 2017), other study ID CKAE609A2202.

A phase 1 evaluation of the pharmacokinetic/pharmacodynamic interaction of the anti-malarial agents KAF156 and piperaquine.

BACKGROUND: KAF156 is a novel imidazolopiperazine anti-malarial with activity against pre-erythrocytic liver stages, asexual and sexual blood stages. Based on in vitro data, a two-way pharmacokinetic interaction was hypothesized for KAF156 use in combination with piperaquine (PPQ) as both drugs are CYP3A4 substrates and inhibitors. Potential combination effects on the QT interval were also assessed. METHODS: This was an open-label, parallel-group, single-dose study in healthy volunteers randomized to three parallel arms (1:1:1) of 800 mg KAF156 + 1280 mg PPQ, 800 mg KAF156 alone and 1280 mg PPQ alone. Triplicate ECGs were done up to 48 h post-dose. Routine safety and pharmacokinetic assessments were carried out up to 61 days. RESULTS: Of the 72 healthy male subjects recruited, 68 completed the study. Co-administration of PPQ and KAF156 had no overall effect on AUC of either compound, but the Cmax values of both KAF156 (~ 23%) and piperaquine (~ 70%) increased. Both drugs given alone or in combination were well tolerated with no deaths or serious adverse events (SAEs). AEs were observed at the frequency of 87.5, 79.2 and 58.3% respectively for KAF156 + PPQ, PPQ and KAF156 arms. The most common AEs were nausea and headache. There were no Grade 3 or 4 events. There were no ECG related AEs, no QTcF interval > 480 ms and no QTcF interval increase from baseline > 60 ms. There was a positive ∆QTcF trend in the KAF156 + PPQ arm when either KAF156 or piperaquine concentration increases, but there was no significant difference between the combination arm and other arms in maximum ∆QTcF. CONCLUSIONS: No safety/cardiac risk or drug interaction was identified which would preclude use of a KAF156 and PPQ combination in future studies.

Estimation of the In Vivo MIC of Cipargamin in Uncomplicated Plasmodium falciparum Malaria.

The MIC of an antimalarial drug for a particular infection is the drug level associated with a net parasite multiplication rate of one per asexual cycle. To ensure the cure of malaria, the MIC must be exceeded until all parasites have been eliminated. The development of highly sensitive and accurate PCR quantitation of low-density malaria parasitemia enables the prospective pharmacokinetic-pharmacodynamic (PK-PD) characterization of antimalarial drug effects and now allows identification of the in vivo MIC. An adaptive design and a PK-PD modeling approach were used to determine prospectively the MIC of the new antimalarial cipargamin (KAE609) in adults with uncomplicated Plasmodium falciparum malaria in an open-label, dose-ranging phase 2a study. Vietnamese adults with acute P. falciparum malaria were allocated sequentially to treatment with a single 30-mg (n = 6), 20-mg (n = 5), 10-mg (n = 7), or 15-mg (n = 7) dose of cipargamin. Artemisinin-based combination therapy was given after parasite densities had fallen and then risen as cipargamin levels declined below the MIC but before a return of signs or symptoms. The rates of parasite clearance were dose dependent, with near saturation of the effect being seen at an adult dose of 30 mg. The developed PK-PD model accurately predicted the therapeutic responses in 23/25 patients. The predicted median in vivo MIC was 0.126 ng/ml (range, 0.038 to 0.803 ng/ml). Pharmacometric characterization of the relationship between antimalarial drug concentrations and parasite clearance rates following graded subtherapeutic antimalarial drug dosing is safe and provides a rational framework for dose finding in antimalarial drug development. (This study has been registered at ClinicalTrials.gov under identifier NCT01836458.).

Bioavailability of Lumefantrine Is Significantly Enhanced with a Novel Formulation Approach, an Outcome from a Randomized, Open-Label Pharmacokinetic Study in Healthy Volunteers.

The artemether-lumefantrine combination requires food intake for the optimal absorption of lumefantrine. In an attempt to enhance the bioavailability of lumefantrine, new solid dispersion formulations (SDF) were developed, and the pharmacokinetics of two SDF variants were assessed in a randomized, open-label, sequential two-part study in healthy volunteers. In part 1, the relative bioavailability of the two SDF variants was compared with that of the conventional formulation after administration of a single dose of 480 mg under fasted conditions in three parallel cohorts. In part 2, the pharmacokinetics of lumefantrine from both SDF variants were evaluated after a single dose of 480 mg under fed conditions and a single dose of 960 mg under fasted conditions. The bioavailability of lumefantrine from SDF variant 1 and variant 2 increased up to ∼48-fold and ∼24-fold, respectively, relative to that of the conventional formulation. Both variants demonstrated a positive food effect and a less than proportional increase in exposure between the 480-mg and 960-mg doses. Most adverse events (AEs) were mild to moderate in severity and not suspected to be related to the study drug. All five drug-related AEs occurred in subjects taking SDF variant 2. No clinically significant treatment-emergent changes in vital signs, electrocardiograms, or laboratory blood assessments were noted. The solid dispersion formulation enhances the lumefantrine bioavailability to a significant extent, and SDF variant 1 is superior to SDF variant 2.

Spiroindolone KAE609 for falciparum and vivax malaria.

BACKGROUND: KAE609 (cipargamin; formerly NITD609, Novartis Institute for Tropical Diseases) is a new synthetic antimalarial spiroindolone analogue with potent, dose-dependent antimalarial activity against asexual and sexual stages of Plasmodium falciparum. METHODS: We conducted a phase 2, open-label study at three centers in Thailand to assess the antimalarial efficacy, safety, and adverse-event profile of KAE609, at a dose of 30 mg per day for 3 days, in two sequential cohorts of adults with uncomplicated P. vivax malaria (10 patients) or P. falciparum malaria (11). The primary end point was the parasite clearance time. RESULTS: The median parasite clearance time was 12 hours in each cohort (interquartile range, 8 to 16 hours in patients with P. vivax malaria and 10 to 16 hours in those with P. falciparum malaria). The median half-lives for parasite clearance were 0.95 hours (range, 0.68 to 2.01; interquartile range, 0.85 to 1.14) in the patients with P. vivax malaria and 0.90 hours (range, 0.68 to 1.64; interquartile range, 0.78 to 1.07) in those with P. falciparum malaria. By comparison, only 19 of 5076 patients with P. falciparum malaria (<1%) who were treated with oral artesunate in Southeast Asia had a parasite clearance half-life of less than 1 hour. Adverse events were reported in 14 patients (67%), with nausea being the most common. The adverse events were generally mild and did not lead to any discontinuations of the drug. The mean terminal half-life for the elimination of KAE609 was 20.8 hours (range, 11.3 to 37.6), supporting a once-daily oral dosing regimen. CONCLUSIONS: KAE609, at dose of 30 mg daily for 3 days, cleared parasitemia rapidly in adults with uncomplicated P. vivax or P. falciparum malaria. (Funded by Novartis and others; ClinicalTrials.gov number, NCT01524341.).

Open-label, single-dose, parallel-group study in healthy volunteers to determine the drug-drug interaction potential between KAE609 (cipargamin) and piperaquine.

KAE609 represents a new class of potent, fast-acting, schizonticidal antimalarials. This study investigated the safety and pharmacokinetics of KAE609 in combination with the long-acting antimalarial piperaquine (PPQ) in healthy volunteers. A two-way pharmacokinetic interaction was hypothesized for KAE609 and PPQ, as both drugs are CYP3A4 substrates and inhibitors. The potential for both agents to affect the QT interval was also assessed. This was an open-label, parallel-group, single-dose study with healthy volunteers. Subjects were randomized to four parallel dosing arms with five cohorts (2:2:2:2:1), receiving 75 mg KAE609 plus 320 mg PPQ, 25 mg KAE609 plus 1,280 mg PPQ, 25 mg KAE609 alone, 320 mg PPQ alone, or 1,280 mg PPQ alone. Triplicate electrocardiograms were performed over the first 24 h after dosing, with single electrocardiograms at other time points. Routine safety (up to 89 days) and pharmacokinetic (up to 61 days) assessments were performed. Of the 110 subjects recruited, 99 completed the study. Coadministration of PPQ had no overall effect on exposure to KAE609, although 1,280 mg PPQ decreased the KAE609 maximum concentration (Cmax) by 17%. The group that received 25 mg KAE609 plus 1,280 mg PPQ showed a 32% increase in the PPQ area under the concentration-time curve from 0 to infinity (AUCinf), while the group that received 75 mg KAE609 plus 320 mg PPQ showed a 14% reduction. Mean changes from baseline in the QT interval corrected by Fridericia's method (QTcF) and the QT interval corrected by Bazett's method (QTcB) with PPQ were consistent with its known effects. PPQ but not KAE609 exposure correlated with corrected QT interval (QTc) increases, and KAE609 did not affect the PPQ exposure-QTc relationship. The QTcF effect for PPQ (least-squares estimate of the difference in mean maximal changes from baseline of 7.47 ms [90% confidence interval, 3.55 to 11.4 ms]) was consistent with the criteria for a positive thorough QT study. No subject had QTcF or QTcB values of >500 ms. Both drugs given alone or in combination were well tolerated, with no deaths, serious adverse events (AEs), or severe AEs reported. Most AEs were mild; upper respiratory tract infections, headache, diarrhea, and oropharyngeal pain were most common. PPQ and KAE609 coadministration had no relevant effect on exposure to either agent, and KAE609 did not affect or potentiate the known effects of PPQ on cardiac conduction.

Increased systemic exposures of artemether and dihydroartemisinin in infants under 5 kg with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (Coartem®).

BACKGROUND: Artemether-lumefantrine (AL) dispersible formulation was developed for the treatment of uncomplicated Plasmodium falciparum malaria in infants and children weighing 5 to <35 kg. However, there are no clinical studies with artemisinin-based combination therapy in infants <5 kg. METHODS: This multicentre, open-label, single-arm study evaluated the efficacy, safety and pharmacokinetics of AL dispersible in infants aged >28 days and <5 kg of body weight, who were treated with one AL dispersible tablet (20 mg artemether/120 mg lumefantrine) given twice-daily for three days and followed up for six weeks (core follow-up) and at 12 months of age (long-term follow-up). RESULTS: A total of 20 patients were enrolled and completed the six-week core study follow-up. In the per protocol population, PCR-corrected cure rate at days 28 and 42 was 100% (95% CI: 79.4, 100). AL dispersible was well tolerated with reported adverse events of mild to moderate severity. Pharmacokinetic data showed that lumefantrine levels were similar, however, artemether and dihydroartemisinin levels were on average two- to three-fold greater than historical values in infants and children ≥5 kg. CONCLUSIONS: A three-day regimen of AL dispersible formulation was efficacious and generally well tolerated in infants weighing <5 kg with uncomplicated P. falciparum malaria, but artemether and dihydroartemisinin exposures could not be supported by the preclinical safety margins for neurotoxicity. Hence, dosing recommendations cannot be made in infants <5 kg as implications for toxicity are unknown. TRIAL REGISTRATION: Clinicaltrials.gov NCT01619878.

A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel antimalarial Spiroindolone KAE609 (Cipargamin) to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers.

This first-in-human randomized, double-blind, placebo-controlled, ascending-single and -multiple oral dose study was designed to evaluate the safety, tolerability, and pharmacokinetics in healthy volunteers of KAE609 (cipargamin; formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single-dose cohorts (1 to 300 mg, including one 30-mg food effect cohort) with 4 to 10 subjects in each cohort and in multiple-dose cohorts (10 to 150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6 to 8 days post-last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of the area under the concentration-time curve from 0 h extrapolated to infinity (AUC0-∞) increased in a dose-proportional manner over the dose range of 1 to 300 mg. The AUC from time zero to the time of the last quantifiable concentration (AUClast) and the maximum concentration of drug in plasma (Cmax) also increased in an approximately dose-proportional manner. When administered daily for 3 days, the accumulation ratio on day 3 (the AUC from time zero to 24 h postdosing [AUC0-24] on day 3/AUC0-24 on day 1) was in the range of 1.5 to 2 in the studied dose range (10 to 150 mg) and was consistent with an elimination half-life of around 24 h. Urine analysis for unchanged KAE609 revealed negligible amounts (≤0.01%) were excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC); however, the Cmax was reduced by around 27%. KAE609 was tolerated in this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses.

Evaluation of two novel tablet formulations of artemether-lumefantrine (Coartem) for bioequivalence in a randomized, open-label, two-period study.

BACKGROUND: Artemether-lumefantrine (Coartem; AL) is a standard of care for malaria treatment as an oral six-dose regimen, given twice daily over three days with one to four tablets (20/120 mg) per dose, depending on patient body weight. In order to reduce the pill burden at each dose and potentially enhance compliance, two novel fixed-dose tablet formulations (80/480 mg and 60/360 mg) have been developed and tested in this study for bioequivalence with their respective number of standard tablets. METHODS: A randomized, open-label, two-period, single-dose, within formulation crossover bioequivalence study comparing artemether and lumefantrine exposure between the novel 80/480 mg tablet and four standard tablets, and the novel 60/360 mg tablet and three standard tablets, was conducted in 120 healthy subjects under fed conditions. Artemether, dihydroartemisinin, and lumefantrine were measured in plasma by HPLC/UPLC-MS/MS. Pharmacokinetic (PK) parameters were determined by non-compartmental analyses. RESULTS: Adjusted geometric mean AUClast for artemether were 345 and 364 ng·h/mL (geometric mean ratio (GMR) 0.95; 90% CI 0.89-1.01) and for lumefantrine were 219 and 218 µg·h/mL (GMR 1.00; 90% CI 0.93-1.08) for 80/480 mg tablet versus four standard tablets, respectively. Corresponding Cmax for artemether were 96.8 and 99.7 ng/mL (GMR 0.97; 90% CI 0.89-1.06) and for lumefantrine were 8.42 and 8.71 µg/mL (GMR 0.97; 90% CI 0.89-1.05). For the 60/360 mg tablet versus three standard tablets, adjusted geometric mean AUClast for artemether were 235 and 231 ng·h/mL (GMR 1.02; 90% CI 0.94-1.10), and for lumefantrine were 160 and 180 µg·h/mL (GMR 0.89; 90% CI 0.83-0.96), respectively. Corresponding Cmax for artemether were 75.5 and 71.5 ng/mL (GMR 1.06; 90% CI 0.95-1.18), and for lumefantrine were 6.64 and 7.61 µg/mL (GMR 0.87; 90% CI 0.81-0.94), respectively. GMR for Cmax and AUClast for artemether and lumefantrine for all primary comparisons were within the bioequivalence acceptance criteria (0.80-1.25). In addition, secondary PK parameters also met bioequivalence criterion. CONCLUSION: Both of the novel artemether-lumefantrine tablet formulations evaluated are bioequivalent to their respective standard Coartem tablet doses. These novel formulations are easy to administer and may improve adherence in the treatment of uncomplicated malaria caused by Plasmodium falciparum. CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2011/12/002256.

Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria.

A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963 (1), which demonstrates potent cellular activity against Pf 3D7 (EC50 = 0.006 µM) and achieves "artemisinin-like" kill kinetics in vitro with a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the Pf-humanized severe combined immunodeficient mouse model. INE963 (1) also exhibits a high barrier to resistance in drug selection studies and a long half-life (T1/2) across species. These properties suggest the significant potential for INE963 (1) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963 (1) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.

Amphotericin-B-loaded polymersomes formulation (PAMBO) based on (PEG)3-PLA copolymers: an in vivo evaluation in a murine model.

This paper deals with in vivo evaluation of a new amphotericin-B-loaded polymersomes (PAMBO) formulation in terms of pharmacokinetics, toxicity, tissue distribution profile, and its efficacy in a murine model of disseminated candidiasis. Pharmacokinetic and tissue distribution studies of the PAMBO showed sustained levels of the drug in plasma as well as in target organs which harbor fungal and leishmanial infection. PAMBO was found to be much less toxic than Fungizone. It was observed that 700% increment in the dose is tolerated without observable toxicity which is supported by survival, biochemical, and histopathological results. PAMBO showed a significant improvement in the survival rate of immunosuppressed mice infected with Candida albicans as compared to control. It also showed better dose to dose (1 mg/kg) efficacy as compared to Fungizone and a significant improvement in the life expectancy at 3 and 5 mg/kg dose levels in the animals. Colony forming unit (CFU) counts in the target organs revealed significant reduction in Candida burden with PAMBO treatment. Kidney, spleen, and lung were cleared of infection, although liver was carrying a very low level of infection. Overall, PAMBO formulation is found to be more efficacious and less toxic in a fungal mice model.

Self assembly of amphiphilic (PEG)(3)-PLA copolymer as polymersomes: preparation, characterization, and their evaluation as drug carrier.

(PEG)(3)-PLA copolymer has been explored for the formation of polymersomes. For this, three chains of methoxy-PEG(1100) were directly attached to citric acid by esterification. (Methoxy-PEG(1100))(3)-citrate was then reacted at its hydroxyl terminal with different moles of d,l-lactide by ring-opening polymerization to obtain polymers with five different PEG-to-PLA ratios ranging from 10:90 to 90:10. Polymers were characterized by GPC, FTIR, (1)H NMR, and DSC, films were characterized for hydrophilicity by contact angle, and surface topography was observed by SEM and AFM. All five polymers were evaluated for the formation of polymersomes. Among these, polymers with PEG content of 10-30% were able to self-assemble into polymersomes. To affirm their self-arrangement and drug carrier properties, hydrophilic and hydrophobic dyes were simultaneously encapsulated in these structures. SEM and TEM analysis of the blank polymersomes confirmed the vesicular nature of the polymersomes, whereas CLSM analysis of dye-loaded polymersomes demonstrated the presence of two separate regions viz. hydrophilic core and hydrophobic wall. Hydrophobic dye, fluorescein was released relatively faster from the wall of polymersomes, whereas hydrophilic dye, propidium iodide, was released in controlled fashion up to 18 days. It is expected that these systems may serve as a suitable carrier for simultaneous or separate delivery of drug molecules with varying physicochemical properties.

Polyanhydrides as localized drug delivery carrier: an update.

BACKGROUND: There is a continuing thrust to increase the efficacy and reduce the toxicity of existing and new drug molecules for their better usage to treat disease. Localized drug delivery has been explored in the same way, which can provide a platform to target local diseased tissues and can reduce the burden on the body by reducing the dose size and hence the dose-related toxicity of the molecules. Various polymers have evolved for the purpose of localized drug delivery, however, polyanhydrides are considered the best, supported by products in the clinical phases. OBJECTIVE: To demonstrate the advantages of localized delivery using basic concepts and describing polyanhydride carrier with products such as Gliadel and Septacin. METHODS: The rationale behind localized drug delivery and the carrier for the same are dealt with. Polyanhydrides discussed in detail are those from subclasses that have been given less emphasis previously and have been developed or investigated in the last 5 years. RESULTS/CONCLUSION: From the recent update on polyanhydrides, it can be concluded that these polymers have great potential as localized drug delivery carriers due to the versatility of their properties. However, the quest to stabilize the system in order to achieve a long shelf life remains ongoing.

Simultaneous determination of hydrazinocurcumin and phenol red in samples from rat intestinal permeability studies: HPLC method development and validation.

Hydrazinocurcumin (HZC) is a patented multiactivity compound and is a potent derivative of curcumin which is not yet explored for further development as formulation and requires the determination of biopharmaceutical suitability of the molecule. Intestinal permeability and logP of a compound are two vital biopharmaceutical properties by which, any "hit" molecule proceeds towards NCE (new chemical entity) and govern formulation design of bioactive molecules. In this report, a simple, precise and accurate isocratic reverse phase (RP) liquid chromatography method for simultaneous analysis of HZC and phenol red, for the application in rat in situ single-pass intestinal perfusion (SPIP) was developed and validated using FDA bioanalytical guidelines. RP-HPLC method was developed on C-18 column with UV detection at 332 nm for both the compounds. Isocratic run with the mobile phase consisting of organic phase (methanol:acetonitrile:: 50:20 v/v) and water in the ratio of 80:20 v/v provided a short run time of 7 min with resolution of more then two without interference of blank matrix. The working/expected concentration range for HZC and phenol red were 0.5-50 and 2-200 microg/ml. LOQs for HZC and phenol red of the method was found to be 0.167 and 0.271 microg/ml respectively. The validation parameters indicate that method was suitable for the intended purpose. Permeability, considering water flux with the help of non-permeable marker phenol red was calculated to be 0.34 x 10(-4)cm/s. Along with other descriptors, logP (1.78) and MW (<500) of HZC makes it a potential candidate for oral formulation.

Copolymers of pharmaceutical grade lactic acid and sebacic acid: drug release behavior and biocompatibility.

Pharmaceutical grade D,L-lactic acid, which is rather an economic source in comparison to lactide monomer, was utilized for synthesis of a series of copolymers with sebacic acid. Polymers were characterized by GPC, FTIR, NMR and DSC techniques, and formulated into blank and methotrexate (MTX) loaded microspheres by emulsion-solvent evaporation method. In vitro degradation of blank microspheres was studied by FTIR, GPC and SEM analysis. MTX loaded microspheres showed the encapsulation efficiency of 44-64% and were in the size range of 40-60 microm. These were used to study the release profile of the encapsulated drug. The release was found to be affected by the pH and buffer concentration of the release medium which was in turn revealed by solubility studies of MTX. The overall study demonstrates significance of drug as well as polymer properties on release. Biocompatibility of polymer was evaluated by injecting microspheres subcutaneously into Sprague-Dawley (SD) rat and no local histopathological abnormalities were found.

A Physiologically Based Pharmacokinetic Model to Describe Artemether Pharmacokinetics in Adult and Pediatric Patients.

Artemether is co-administered with lumefantrine as part of a fixed-dose combination therapy for malaria in both adult and pediatric patients. However, artemether exposure is higher in younger infants (1-3 months) with a lower body weight (<5 kg) as compared to older infants (3-6 months) with a higher body weight (≥5 to <10 kg), children, and adults. In contrast, lumefantrine exposure is similar in all age groups. This article describes the clinically observed artemether exposure data in pediatric populations across various age groups (1 month to 12 years) and body weights (<5 or ≥5 kg) using physiologically based pharmacokinetic (PBPK) mechanistic models. A PBPK model was developed using artemether physicochemical, biopharmaceutic, and metabolic properties together with known enzyme ontogeny and pediatric physiology. The model was verified using clinical data from adult patients after multiple doses of oral artemether, and was then applied to simulate the exposure in children and infants. The simulated PBPK concentration-time profiles captured observed clinical data. Consistent with the clinical data, the PBPK model simulations indicated a higher artemether exposure for younger infants with lower body weight. A PBPK model developed for artemether reliably described the clinical data from adult and pediatric patients.

Role of polyanhydrides as localized drug carriers.

Many drugs that are administered in an unmodified form by conventional systemic routes fail to reach target organs in an effective concentration, or are not effective over a length of time due to a facile metabolism. Various types of targeting delivery systems and devices have been tried over a long period of time to overcome these problems. Targeted delivery or localized drug delivery offers an advantage of reduced body burden and systemic toxicity of the drugs, especially useful for highly toxic drugs like anticancer agents. Local drug delivery via polymer is a simple approach and hypothesized to avoid the above stated problems. Polyanhydrides are a unique class of polymer for drug delivery because some of them demonstrate a near zero order drug release and relatively rapid biodegradation in vivo. Further, the release rate of polyanhydride fabricated device can be altered over a thousand fold by simple changes in the polymer backbone. Hence, these are one of the best-suited polymers for drug delivery, with biodegradability and biocompatibility. The review focuses on the advantages of polyanhydride carriers in localized drug delivery along with their degradability behavior, toxicological profile and role in various disease conditions.

Self assembling polymers as polymersomes for drug delivery.

Polymersomes are one of the most interesting and versatile architectures among various self assembled systems for drug delivery. The stability and ability to load both hydrophilic and hydrophobic molecules make them excellent candidates to use as drug delivery systems. They demand for certain physicochemical parameters; especially hydrophilic to hydrophobic block ratio of copolymer to form vesicular morphologies. Different amphiphilic copolymers as well as their architectures show differences in the requirement of hydrophilic to hydrophobic block ratio to form polymersomes with various types of morphologies. This review focuses on basic the aspects of polymersomes along with a series of copolymers employed for preparation of polymersomes and their potential applications as drug delivery systems.

Development of amphotericin B loaded polymersomes based on (PEG)(3)-PLA co-polymers: Factors affecting size and in vitro evaluation.

Amphotericin B (AmB) is a broad spectrum antifungal and antileishmenial agent and its clinical use is limited due to substantial dose limiting toxicities such as nephrotoxicity. In this work, amphotericin B is formulated in polymersomes of branched (PEG)(3)-PLA co-polymer. Polymersomes were prepared by solvent injection method and the effects of various formulation and process parameters on size and size distribution were studied. The results showed that viscosity of biphasic solution during formulation has significant influence on the size and size distribution of the polymersomes. Further, drug-loaded polymersomes with size of 199.6+/-14.1nm, PDI of 0.258+/-0.18, zeta potential (zeta) of -18.07+/-4.91mV and loading of 16.26+/-2.50% were obtained. Drug was found to be intercalated in the wall of polymersomes as observed using FITC tagged drug and CLSM study. An in vitro release media containing sodium deoxycholate was developed and a significant amount of drug release was observed up to 24h there after a very slow release was obtained. Free drug was not found in the formulation and different molecular forms of the drug (AmB) were observed by UV-visible spectroscopy and circular dichroism. This was further supported by hemolysis experiments, where negligible hemolysis in the test formulation was observed as compared to 100% hemolysis in a marketed formulation (Fungizone).