Responsive Sensory Evaluation to Develop Flexible Taste-Masked Paediatric Primaquine Tablets against Malaria for Low-Resource Settings

Ranmal, Sejal R.; Lavarde, Marc; Wallon, Elodie; Issa, Samar; Taylor, Walter R.; Nguyen Ngoc Pouplin, Julie L. A.; Tuleu, Catherine; Pensé-Lhéritier, Anne-Marie

doi:10.3390/pharmaceutics15071879

Cited by 6 publications

(5 citation statements)

References 37 publications

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“…Results also differed across participants for 6-MF, which was less able to reduce bitterness overall compared with sucralose. Sweeteners at high concentrations have been widely used in medicine formulations as partly effective bitter-reducing excipients [22, 53], due to their bitter-masking and potential blocking effects [54]; sucralose also had a greater bitter suppression than other flavoring agents, taste modifiers, and bitter blockers in formulations of primaquine, an important antimalarial drug [16].…”

Section: Discussionmentioning

confidence: 99%

“…For example, early human sensory studies of the bitter-tasting antimalarial drug quinine showed person-to-person differences [12], and like color-blindness, genetic differences at least partially account for some people tolerating its taste [13][14][15]. The most sensitive quinine genotype differs by ancestry, but ancestry is often overlooked in quinine sensory tests [16]. As another example, the thyroid medications methimazole [17] and propylthiouracil (PROP) [18] markedly differ in bitterness ratings owing to genetic variation.…”

Section: Introductionmentioning

confidence: 99%

“…For methimazole, the insensitive variant is present in about half of humans worldwide [19], but it is concentrated in people in specific geographic regions [20] -a result foreshadowed by early anthropologists who studied the taste of similar chemicals like PROP and phenylthiocarbamide [21]. Experts in the area of drug formulation have considered the effects of age on drug palatability, but rarely ancestry [16,[22][23][24]. Therefore, we hypothesize not only that the study of bitter medicines will uncover large personto-person differences but also that these differences could correlate with geographic ancestry and genotype.…”

Section: Introductionmentioning

confidence: 99%

“…For methimazole, the insensitive variant is present in about half of humans worldwide [19], but it is concentrated in people in specific geographic regions [20] – a result foreshadowed by early anthropologists who studied the taste of similar chemicals like PROP and phenylthiocarbamide [21]. Experts in the area of drug formulation have considered the effects of age on drug palatability, but rarely ancestry [16, 22-24].…”

Section: Introductionmentioning

confidence: 99%

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Worldwide study of the taste of bitter medicines and their modifiers

Nguyen,

Lin,

Bell

et al. 2024

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The bitter taste of medicines hinders patient compliance, but not everyone experiences these difficulties because people worldwide differ in their bitterness perception. To better understand how people from diverse ancestries perceive medicines and taste modifiers, 338 adults, European and recent US and Canada immigrants from Asia, South Asia, and Africa, rated the bitterness intensity of taste solutions on a 100-point generalized visual analog scale and provided a saliva sample for genotyping. The taste solutions were five medicines, tenofovir alafenamide (TAF), moxifloxacin, praziquantel, amodiaquine, and propylthiouracil (PROP), and four other solutions, TAF mixed with sucralose (sweet, reduces bitterness) or 6-methylflavone (tasteless, reduces bitterness), sucralose alone, and sodium chloride alone. Bitterness ratings differed by ancestry for two of the five drugs (amodiaquine and PROP) and for TAF mixed with sucralose. Genetic analysis showed that people with variants in one bitter receptor variant gene (TAS2R38) reported PROP was more bitter than did those with a different variant (p= 7.6e-19) and that people with either an RIMS2 or a THSD4 genotype found sucralose more bitter than did others (p=2.6e-8, p=7.9e-11, resp.). Our findings may help guide the formulation of bad-tasting medicines to meet the needs of those most sensitive to them.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Worldwide study of the taste of bitter medicines and their modifiers

Nguyen,

Lin,

Bell

et al. 2024

Preprint

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“…Macleods in India prequalified their coated 15 mg tablet in December last year (2023) and the Medicines for Malaria Venture is supporting Fosun, a Chinese company, to develop 2.5 and 5 mg dispersible tablets of PQ [ 28 ]. A consortium, led by this paper’s first and senior authors, is also planning to prequalify a line of flavoured paediatric PQ tablets (2.5, 5 and 7.5 mg) by showing bioequivalence of a flavoured 15 mg tablet in adults and then obtaining a biowaiver on the basis of proportionality of the lower tablet strengths compared to the 15 mg tablet [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Bioequivalence of a new coated 15 mg primaquine formulation for malaria elimination

Nguyen Ngoc Pouplin,

Kaendiao,

Rahimi

et al. 2024

Malar J

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Background With only one 15 mg primaquine tablet registered by a stringent regulatory authority and marketed, more quality-assured primaquine is needed to meet the demands of malaria elimination. Methods A classic, two sequence, crossover study, with a 10-day wash out period, of 15 mg of IPCA-produced test primaquine tablets and 15 mg of Sanofi reference primaquine tablets was conducted. Healthy volunteers, aged 18–45 years, without glucose-6-phosphate dehydrogenase deficiency, a baseline haemoglobin ≥ 11 g/dL, creatinine clearance ≥ 70 mL/min/1.73 ms, and body mass index of 18.5–30 kg/m2 were randomized to either test or reference primaquine, administered on an empty stomach with 240 mL of water. Plasma primaquine and carboxyprimaquine concentrations were measured at baseline, then 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 h by liquid chromatography coupled to tandem mass spectrometry. Primaquine pharmacokinetic profiles were evaluated by non-compartmental analysis and bioequivalence concluded if the 90% confidence intervals (CI) of geometric mean (GM) ratios of test vs. reference formulation for the peak concentrations (Cmax) and area under the drug concentration–time (AUC0–t) were within 80.00 to 125.00%. Results 47 of 50 volunteers, median age 33 years, completed both dosing rounds and were included in the bioequivalence analysis. For primaquine, GM Cmax values for test and reference formulations were 62.12 vs. 59.63 ng/mL, resulting in a GM ratio (90% CI) of 104.17% (96.92–111.96%); the corresponding GM AUC0–t values were 596.56 vs. 564.09 ngxh/mL, for a GM ratio of 105.76% (99.76–112.08%). Intra-subject coefficient of variation was 20.99% for Cmax and 16.83% for AUC0–t. Median clearances and volumes of distribution were similar between the test and reference products: 24.6 vs. 25.2 L/h, 189.4 vs. 191.0 L, whilst the median half-lives were the same, 5.2 h. Conclusion IPCA primaquine was bioequivalent to the Sanofi primaquine. This opens the door to prequalification, registration in malaria endemic countries, and programmatic use for malaria elimination. Trial registration The trial registration reference is ISRCTN 54640699

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