Fixed Combination Products Research Articles

A combination of carbonates and Opuntia ficus-indica extract protects esophageal cells against simulated acidic and non-acidic reflux in vitro

Buffering of stomach acid by antacids is a well-established symptomatic therapy for heartburn. In addition, preparations from prickly pear (Opuntia ficus-indica) have been shown to reduce tissue damage in experimental gastritis models and to attenuate gastrointestinal discomfort in patients. Both active principles have been included in a fixed-combination product for symptomatic treatment of heartburn containing carbonate antacids (CaCO3 and MgCO3) and an extract from Opuntia ficus-indica cladodes. The aim of the study was to characterize the acid neutralization and esophageal cell protective activities of the product and its individual active ingredients in a set of in vitro assays. Acid neutralization was assessed in a simulated stomach model. Protective activity of individual constituents and in combination was analyzed in an esophageal cell line (COLO-680 N) exposed to low pH and deoxycholic acid to simulate acidic and non-acidic reflux challenge. The combination product protected cells against low pH mediated cytotoxicity via acid neutralization by carbonates. Opuntia extract itself and the combination product attenuated bile acid-induced cell irritation as measured by reduced release of proinflammatory interleukin-6 and -8. In conclusion, addition of Opuntia extract to a mineral antacid provides dual protection against acidic and non-acidic simulated reflux challenge.

Trends in antihypertensive use among privately insured hypertensive clients in Ghana.

The objective of the study was to describe the patterns of antihypertensive medicines (AHM) in a selected national population in Ghana. The claims data for all privately insured patients in Ghana over three years to 2018 were analysed. The classes of medicines used, the dose by time, gender and age, and generic status were examined. In addition, the use in Defined Daily Dose (DDD) per 1000 population per day was estimated. Classes of AHM prescribed were CCB, ARB, ACEI, diuretics, and BB. Amlodipine, nifedipine, losartan, lisinopril, and bendroflumethiazide accounted for 74% of all use. The most widely used single CCB was amlodipine 3.92 DDD/1,000 population/day in 2016, 3.92 DDD/1,000 population/day in 2017, and 4.92 DDD/1,000 population/day in 2018. In those aged 51-60 years, use of CCB in women (74.0 DDD/1,000 population/day) was almost twice that of men (38.3 DDD/1,000 population/day). The top ten medicines accounted for 93% of all single medicine products in 2018. Most single medicine products was generic (76.5% in 2016; 79.9% in 2017 and 83.1% in 2018) whiles most fixed combination products were branded (73.0% in 2016; 89.7% in 2017 and 91.3% in 2018). The patterns of AHM use are clinically expected although the Ghana Standard Treatment guidelines are not directive about lines of treatment.

Co-formulation of ketoprofen with tulathromycin alters pharmacokinetic and pharmacodynamic profile of ketoprofen in cattle.

The current studies aimed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) profile and to establish a PK-PD model for ketoprofen in a new fixed combination product containing tulathromycin (2.5mg/kg) and ketoprofen (3mg/kg) to treat bovine respiratory disease associated with pyrexia in cattle. Firstly, the effect of different ketoprofen doses as mono-substance (1, 3, and 6mg/kg subcutaneous) on lipopolysaccharide-induced fever was evaluated which indicated that rectal temperature reduction lasted longer in the calves receiving 3 and 6mg/kg ketoprofen. Secondly, the PK profile of the combination product was compared with mono-substance products (3mg/kg subcutaneous and intramuscular). The PK profile of ketoprofen in the combination product was characterized by longer t1/2 , lower Cmax and increased AUC in comparison with mono-substance products. Due to prolonged ketoprofen exposure in the combination product, the pyrexia reducing effect of the combination product lasted longer in a second lipopolysaccharide challenge study in comparison with mono-substance products. Finally, a PK-PD model for the anti-pyretic effect of ketoprofen was developed based on the data from the different studies. The PK-PD model eliminated the need for additional animal experiments and indicated that a 3mg/kg ketoprofen dose in the combination product provided optimal efficacy.

Choice of progestogen for endometrial protection in combination with transdermal estradiol in menopausal women.

Transdermal estradiol (TE) application (using gels, patches or a novel spray) is now a preferred route of hormone therapy (HT) in menopausal women, because various risks such as venous thromboembolism, stroke and unwanted hepatic effects can be reduced compared with oral HT. However, in the presence of an intact uterus, concurrent administration of progestogen is needed for endometrial protection. Due to the variety of progestogens available and differences in their clinical effects, the selection of the most appropriate substance and dosing for individual combination therapy can be difficult. This is especially true for TE gels and the novel spray because no fixed combination products are commercially available, meaning all progestogens must be added separately, and even for patches only two transdermal synthetic progestogens are available. The aim of this review was to summarize data on the endometrial effects of the different progestogens and to provide practical recommendations for the choice of progestogen (type and dosing), with a focus on endometrial protection when using TE, especially when using the novel estradiol (E2) spray.

Incidence of Pyrrolizidine Alkaloids in Herbal Medicines from German Retail Markets: Risk Assessments and Implications to Consumers.

The occurrence of potentially toxic pyrrolizidine alkaloids (PAs) in herbal medicines (HMs) is currently intensely being discussed in Europe. Pyrrolizidine alkaloids, particularly the 1,2-unsaturated PAs, are undesired compounds in HMs due to their potential hepatotoxic and carcinogenic properties. In this study, 98 widely patronized HMs from six popular German retail supermarkets/drugstores, as well as from pharmacies, were analyzed by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry for the presence of PAs. The results showed that about 63% of the HMs were PA positive, whereas the average PA concentration of the samples was 201μg/kg, the highest concentration of PAs (3270μg/kg) was attributed to a product that was purchased from the pharmacy and contained Hypericum perforatum L. (St. John's Wort) as an active ingredient. In addition, H. perforatum-containing products were frequently contaminated with PAs from Echium spp., while both Cynara cardunculus L. products and fixed-combination products of Gentiana lutea L., Rumex acetosa L., Verbena officinalis L., Sambucus nigra L., and Primula veris L. products were commonly contaminated with PAs of Senecio spp. The study showed that H. perforatum, C. cardunculus, Urtica dioica L., and fixed-combination products were frequently contaminated with PA levels above the recommended values of both the German and European Medicines Agencies. Copyright © 2017 John Wiley & Sons, Ltd.

Arterial Hypertension and Optimization of Medication Prevention of Ischemic Stroke

The article is devoted to the actual problem - the prevention of stroke in patients with arterial hypertension (AH). Mechanisms of cerebral complications of AH, the key areas of prevention of stroke are presented. On the basis of earlier large randomized trials justified the use of fixed combination products (polypills) comprising, along with antihypertensive lipid-lowering drugs, which is the key to improving treatment adherence and effectiveness of pharmacological prevention of stroke.

Calcipotriol and betamethasone dipropionate exert additive inhibitory effects on the cytokine expression of inflammatory dendritic cell–Th17 cell axis in psoriasis

BackgroundPsoriasis vulgaris is characterised by epidermal hyper-proliferation and infiltration of immune cells including dendritic cells (DCs) and T cells. The inflammation is driven by a complex interplay between immune and skin cells involving interleukin (IL)-17A, IL-23 and TNF-α as key drivers. The calcipotriol/betamethasone dipropionate two-compound fixed combination product is widely used for topical treatment of psoriasis. However, the mechanism behind its high efficacy has not been elucidated in detail. ObjectiveHere, we investigated and compared the immune modulatory effects of betamethasone, calcipotriol and the combination in ex vivo cultures of psoriatic skin and in vitro cultures of primary human cells that recapitulate key cellular activities of psoriatic inflammation. MethodThe immune modulatory effect of the treatments on psoriatic skin and on in vitro differentiated Th1/Th17 cells, Tc1/Tc17 cells, monocyte-derived inflammatory dendritic cells and primary keratinocytes was assessed by a panel of inflammatory and phenotypic related transcription factors and cytokines. The expression was evaluated by both gene and protein analysis. ResultsCompared to vehicle control or mono-treatments, the effect of calcipotriol/betamethasone combination was significantly better in inhibiting the secretion of IL-17A and TNF-α in psoriatic skin. Additionally, the two components showed additive inhibitory effects on secretion of IL-23 and TNF-α by DCs, of IL-17A and TNF-α by both CD4+ and CD8+ T cells and reduced inflammatory responses in Th17-stimulated keratinocytes. Furthermore, calcipotriol was found to enhance IL-10 secretion in psoriatic skin and in human T cells, to induce secretion of type 2 cytokines by T cells and, lastly, to significantly modulate the differentiation of DCs and T cells. ConclusionsIn summary, we demonstrate a unique and supplementary immune modulatory effect of calcipotriol/betamethasone combination on TNF-α and IL-23/Th17 immune axis, supporting the superior clinical efficacy of the combination product compared to the respective mono-treatments in psoriasis patients.

Artemisinin-based combination therapy in the treatment of uncomplicated malaria: review of recent regulatory experience at the European Medicines Agency.

Malaria remains a major public health challenge with almost half of the world's population exposed to the risk of contracting the illness. Prompt, effective and well tolerated treatment remains one of the cornerstones in the disease management, with artemisinin-based combination therapy the recommended option for non-severe malaria in endemic areas with predominant Plasmodium falciparum infections.Recent experience has been obtained at the European Medicines Agency with regulatory approval of two such antimalarial fixed combination products. For these cases, two different regulatory pathways were applied. As such, the present contribution describes this experience, emphasising main differences and applicability offered by these regulatory choices.

Fixed-Dose Combination of Tafluprost and Timolol in the Treatment of Open-Angle Glaucoma and Ocular Hypertension: Comparison with Other Fixed-Combination Products

A new preservative-free fixed-dose combination of 0.0015% tafluprost, a prostaglandin F2α analog, and 0.5% timolol (TAF/TIM; Santen Oy, Tampere, Finland), a beta-adrenergic antagonist has recently been developed. The intraocular pressure (IOP) reduction with TAF/TIM in open-angle glaucoma and ocular hypertension is similar to that of other prostaglandin–timolol fixed-combination products. Patients with high IOP responded well to TAF/TIM with reductions of up to 40% (>13 mmHg) and beyond. Compared to previous controlled and double-masked clinical trials with DuoTrav® (Alcon, Fort Worth, USA) and Ganfort® (Allergan, Irvine, USA), TAF/TIM caused less superficial ocular side effects and less conjunctival hyperemia. Plausible explanations for the differences in side effects between the fixed-combination products are discussed.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-014-0151-7) contains supplementary material, which is available to authorized users.

Adjunctive therapy patterns in glaucoma patients using prostaglandin analogs.

PurposeTo analyze patterns of use of adjunctive therapies among new initiators of topical prostaglandin analogs (PGAs) in a managed care population.MethodsThe study cohort included patients in a claims database who initiated PGA therapy between June 2007 and April 2011. Patients who had one or more adjunctive therapy prescriptions during 24 months of follow-up were included. Patterns of adjunctive therapy use were identified and compared between patients who had one or two fills of the initial adjunctive therapy and those who had three or more.ResultsThere were 16,486 eligible beneficiaries. Of these, 5,933 (36%) had one or more adjunctive therapies within 24 months from the start of the PGA, 82% of whom started adjunctive therapy within 12 months. About 28% of patients started adjunctive therapy with a fixed-combination product; 45% of these patients started within the first 30 days. Overall, a large number of patients (42%) required adjunctive therapy within 30 days. Twenty-five percent of patients had only one or two prescriptions of their initial adjunctive therapy; of these patients, 74% discontinued adjunctive therapy altogether.ConclusionApproximately 30% of patients starting glaucoma therapy will require adjunctive therapy within 1 year, and many receive a fixed-combination product as initial adjunctive therapy shortly after starting glaucoma therapy. This suggests a prescribing trend toward earlier, more aggressive drug therapy to control pressure and minimize disease progression. We found that compliance with adjunctive therapy continues to be a problem for patients, which could be attributed to a number of treatment burden and economic factors.

PRS1 - Characteristics of Patients with Chronic Obstructive Pulmonary Disease (COPD) Receiving Inhaled Corticosteroid/Long-Acting b2-ß2-agonist (ICS/LABA) Fixed Combination Products in English Primary Care

PRS1 - Characteristics of Patients with Chronic Obstructive Pulmonary Disease (COPD) Receiving Inhaled Corticosteroid/Long-Acting b2-ß2-agonist (ICS/LABA) Fixed Combination Products in English Primary Care

Reducing pill burden and helping with medication awareness to improve adherence

Medication nonadherence can be intentional when polypharmacy and high pill burden become overwhelming for patients. At the Bruyere Geriatric Day Hospital (GDH), patients referred for medication review take an average of 15 medications.1 The resulting complex regimens can lead to confusion about indications for medications, lack of certainty in their effectiveness and frustration. Patients increasingly believe that the multiple medications may not be needed and often elect to stop taking some or all of them. This case illustrates an approach to reducing the pill burden of polypharmacy that includes eliminating medications that are not working or are potentially harmful, reducing dosing frequency and using fixed combination products. Ultimately, identifying barriers to adherence and enhancing the patient’s understanding of the indication and proper use of medications, while reducing pill burden, assisted in improving adherence and disease control during a 12-week admission. A description of the GDH processes and in particular, communication about medication-related care, can be found in Appendix 1 (www.cpjournal.ca).

Removal of preservative from Ganfort improves intraocular pressure (IOP) lowering in patients – A timolol dose‐response phenomenon

AbstractPurpose A benzalkonium chloride (BAK)‐free fixed‐combination formulation of bimatoprost and timolol (Ganfort) has been developed for patients who are sensitive to preservatives. A randomized controlled study in 561 patients compared the IOP‐lowering efficacy of the BAK‐free formulation versus the preserved Ganfort. At all timepoints, IOP lowering, numerically, consistently favoured the BAK‐free formulation. This finding contradicted expectations that the removal of BAK would result in lower ocular bioavailability of both bimatoprost and timolol, resulting in less efficacy. Research was conducted to explore possible explanation for the clinical observation.Methods Literature search on timolol dose response was performed, focusing on IOP lowering following topical dosing of 0.1%, 0.25%, and 0.5% timolol ophthalmic solutions.Results A U‐shaped dose‐response curve exists for timolol, and available data suggest that the dose that elicits maximal IOP lowering lies between 0.25% and 0.5%.Conclusion Removal of BAK from the fixed combination product Ganfort, which contains 0.5% timolol, may have resulted in a lower, but optimal, ocular concentration of timolol, leading to improved IOP‐lowering efficacy with the preservative‐free formulation. Commercial interest

Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Zidovudine (Azidothymidine)

Literature data on the properties of zidovudine relevant to waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate-release (IR) solid oral dosage forms containing zidovudine alone or in combination with other active pharmaceutical ingredients (APIs) are reviewed. Solubility, dissolution, and permeability data for zidovudine, along with its dosing schedule, therapeutic index and pharmacokinetic properties, and reports related to BE/bioavailability were all taken into consideration. Data for solubility and permeability suggest that zidovudine belongs to Class I according to the Biopharmaceutics Classification System. Also, zidovudine is not a narrow therapeutic index drug. Although five out of 13 formulations tested in vivo (mostly of unreported composition) failed to show BE, it appears that in vitro studies performed according to biowaiver methods could predict in vivo behavior. Nevertheless, it is highly recommended that if a biowaiver is to be applied, excipient choices be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form (Table 2 of this monograph), in their usual amounts. These conclusions apply to products containing zidovudine as the only API and also to fixed combination products containing zidovudine with respect to the zidovudine component of the formulation.

Newer Approaches to the Treatment of Acne Vulgaris

The multifactorial etiology of acne vulgaris makes it challenging to treat. Current treatments include topical retinoids, benzoyl peroxide, topical and systemic antibiotics, azelaic acid, and systemic isotretinoin. Adjunctive and/or emerging approaches include topical dapsone, taurine bromamine, resveratrol, chemical peels, optical treatments, as well as complementary and alternative medications. The purpose of this paper is to discuss the therapies available for acne and their latest developments, including new treatment strategies (i.e. re-evaluation of the use of oral antibiotics and avoidance of topical antibiotic monotherapy, use of subantimicrobial antibiotic dosing, use of low-dose isotretinoin, optical treatments), new formulations (microsponges, liposomes, nanoemulsions, aerosol foams), new combinations (fixed-combination products of topical retinoids and topical antibiotics [essentially clindamycin] or benzoyl peroxide), new agents (topical dapsone, taurine bromamine, resveratrol) and their rationale and likely place in treatment. Acne vaccines, topical natural antimicrobial peptides, and lauric acid represent other promising therapies.

Clinical utility of azilsartan-chlorthalidone fixed combination in the management of hypertension.

Azilsartan–chlorthalidone fixed combination is a new drug in the management of hypertension. Azilsartan has been shown to have greater blood pressure-lowering effects than other angiotensin-receptor blockers (ARBs), and the debate regarding the superiority of chlorthalidone over hydrochlorothiazide has been ongoing for years. The combination is unique because it is the first to partner an ARB with this, possibly more effective, diuretic. This review will address trials involving both components of this drug, as well as phase III trials involving the fixed-combination product. The article will also discuss the benefit of combination therapy in the treatment of hypertension.

Stability-indicating HPLC-DAD/UV-ESI/MS impurity profiling of the anti-malarial drug lumefantrine

BackgroundLumefantrine (benflumetol) is a fluorene derivative belonging to the aryl amino alcohol class of anti-malarial drugs and is commercially available in fixed combination products with β-artemether. Impurity characterization of such drugs, which are widely consumed in tropical countries for malaria control programmes, is of paramount importance. However, until now, no exhaustive impurity profile of lumefantrine has been established, encompassing process-related and degradation impurities in active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs).MethodsUsing HPLC-DAD/UV-ESI/ion trap/MS, a comprehensive impurity profile was established based upon analysis of market samples as well as stress, accelerated and long-term stability results. In-silico toxicological predictions for these lumefantrine related impurities were made using Toxtree® and Derek®.ResultsSeveral new impurities are identified, of which the desbenzylketo derivative (DBK) is proposed as a new specified degradant. DBK and the remaining unspecified lumefantrine related impurities are predicted, using Toxtree® and Derek®, to have a toxicity risk comparable to the toxicity risk of the API lumefantrine itself.ConclusionsFrom unstressed, stressed and accelerated stability samples of lumefantrine API and FPPs, nine compounds were detected and characterized to be lumefantrine related impurities. One new lumefantrine related compound, DBK, was identified and characterized as a specified degradation impurity of lumefantrine in real market samples (FPPs). The in-silico toxicological investigation (Toxtree® and Derek®) indicated overall a toxicity risk for lumefantrine related impurities comparable to that of the API lumefantrine itself.

Efficacy and tolerability of the fixed combination of brinzolamide 1% and timolol 0.5% in daily practice

Introduction:The purpose of this study was to document the efficacy and tolerability of the new fixed-combination (FC) brinzolamide 1%/timolol 0.5% as used in daily practice throughout Germany.Methods:An open-label, multicenter, observational study of patients was performed that evaluated the transition from prior medication to brinzolamide/timolol FC for the reduction of intraocular pressure (IOP). Ophthalmologists measured IOP at baseline and 4–6 weeks after transition and assessed their satisfaction with brinzolamide/timolol FC. Patients assessed the tolerability of both their previous and new regimens, judged their satisfaction with brinzolamide/timolol, and reported their preference between their previous and new regimens. Patients transitioning from other FC products to brinzolamide/timolol FC were analyzed separately.Results:Data from 14,025 patients from 1161 centers were analyzed. Four to 6 weeks after transition to brinzolamide/timolol, patients experienced a mean IOP decrease of 3.9 ± 4.3 mm Hg (P < 0.0001). All of the predefined patient subgroups (grouped by previous therapy) demonstrated a significant mean IOP reduction following transition to brinzolamide/timolol (P < 0.0001). Patients judged brinzolamide/timolol tolerability more positively than they did their previous therapies (87.2% vs 53.7% favorable assessments) and reported a high satisfaction rating with brinzolamide/timolol (93.4%). Brinzolamide/timolol was preferred over previous therapy at a ratio of almost 9:1. Patients who transitioned from dorzolamide/timolol to brinzolamide/timolol (n = 2937) demonstrated a significant decrease in mean IOP (P < 0.0001), rated brinzolamide/timolol more tolerable than dorzolamide/timolol (88.9% vs 28.9%), and preferred brinzolamide/timolol at a ratio of more than 9:1. Patients who transitioned from brimonidine/timolol (n = 209) demonstrated a significant decrease in mean IOP (P < 0.0001), rated brinzolamide/timolol more tolerable (86.5% vs 32.1%), and preferred brinzolamide/timolol at a ratio of 11.5:1.Conclusions:The FC brinzolamide 1%/timolol 0.5% produced better IOP control than all previous therapies analyzed and demonstrated favorable tolerability and a high satisfaction rating, resulting in a strong patient preference for brinzolamide/timolol over previous therapies.

Diphenhydramine dose–response: a novel approach to determine triage thresholds

Context. It is unclear how much diphenhydramine (DPH) is toxic in humans. Previous dose–response studies have had conflicting results. Objective. We sought to evaluate DPH dose–response using a unique method that utilizes acetaminophen (APAP) serum concentrations to estimate DPH doses in patients ingesting APAP/DPH in a fixed-combination product. Methods. We retrospectively analyzed APAP/DPH-only exposures in patients 2–80 years of age using case data from 15 U.S. poison centers. DPH dose was extrapolated from measured serum APAP concentrations. A clinically significant response (CSR) was predefined in terms of eight specific manifestations (e.g., coma) that would warrant emergency department intervention. Nominal logistic regression was used to model the probability of each recorded manifestation across DPH dose ranges examining fits for mg, mg/kg, log10 mg, and log10 mg/kg DPH doses. The threshold value where patients reliably became symptomatic was determined by further examining receiver operating characteristic curves. Results. There were 509 cases that met inclusion criteria. Forty-five patients (9%) developed CSRs. A higher percentage of patients developed CSR at ≥ 7.5 mg/kg DPH and ≥1 g total DPH cutoff points (p < 0.05, Fisher's exact test). The best model for predicting the probability of CSR was a logistic fit of log10 mg/kg dose (p < 0.05). By this model, for every 1 log10 unit increase of mg/kg DPH dose, the odds of developing a CSR increased 47-fold (95% CI 17, 154). Receiver operating characteristic analyses showed a dose-related progression of symptoms. The cut-point with greatest sensitivity (98%) versus 1-specificity (57%) corresponded to an extrapolated mg/kg DPH dose of 8.2 mg/kg (95% CI 5.6, 10.5). Conclusion. Our findings support the current American Association of Poison Control Centers' guideline recommendation to refer patients to the hospital for evaluation if they have ingested greater than or equal to 7.5 mg/kg of DPH.

Pharmacokinetics and Comparative Bioavailability of Artesunate and Mefloquine Administered Separately or as a Fixed Combination Product to Healthy Volunteers and Patients with Uncomplicated Plasmodium falciparum Malaria.

Purpose: The current World Health Organization recommendation for the treatment of uncomplicated Plasmodium falciparum malaria is with artemisinin-based combination therapy. Artesunate and mefloquine combination therapy has achieved consistently high efficacy rates and reduced malaria morbidity; however, the current standard treatment regimen is complex and may be difficult to comply with outside of a research setting. Consequently, an artesunate mefloquine fixed dose oral co-formulation has been developed and is now registered in Brazil. This study was conducted in order to assess the pharmacokinetics and comparative bioavailabilities of artesunate and mefloquine administered as separate products and the new co-formulated product. Methods: The pharmacokinetics of artesunate, dihydroartemisinin, the artesunate metabolite and predominant species and mefloquine were assessed in a single-dose, randomised, crossover design study in healthy volunteers and in a multiple-dose, randomised, parallel group study in patients with uncomplicated falciparum malaria. Results: For artesunate/dihydroartemisinin the lower bound of the 90% confidence intervals for the comparison between co-formulated and separate products extended below the 80% bioequivalence limit; area under the curve and Cmax values were 15-25% and 25-40% lower than those observed after administration of the separate products. The two formulations were bioequivalent in terms of mefloquine pharmacokinetics in uncomplicated falciparum malaria patients; the 90% confidence intervals for dose-normalised area under the curve (AUClast and AUCinf) and maximum observed concentration (Cmax) were within the 80 - 125% limits. In contrast, mefloquine area under the curve and Cmax values were 15% and 30% lower for the co-formulated products compared to the separate products in healthy volunteers. Conclusions: These differences in the exposure to artesunate, dihydroartemisinin and mefloquine are unlikely to be of clinical relevance based on in vitro and clinical data. However, the results of this study do emphasise the importance of evaluating the bioavailability and bioequivalence of new formulations, particularly in specific patient groups.