Bioavailability of Hydroxychloroquine Tablets Assessed with Deconvolution Techniques

doi:10.1002/jps.2600810211

Journal of Pharmaceutical Sciences

Volume 81, Issue 2, February 1992, Pages 155-159

https://doi.org/10.1002/jps.2600810211 Get rights and content

Abstract

Four deconvolution methods (staircase, delta function, and least squares methods using single and sequential first-order input functions) were used to assess the absolute bioavailability of hydroxychloroquine tablets in nine healthy fasting volunteers. The volunteers received, in a random crossover design, a 155-mg oral tablet and a 155-mg iv infusion of racemic hydroxychloroquine. The mean fractions of the dose absorbed, calculated using the four deconvolution methods, were not statistically different (p = 0.70). The mean fraction absorbed (±SD) was 0.67 ± 0.12, which was not significantly different from that reported previously in a conventional bioavailability study (p = 0.22). The mean absorption half-life was calculated to be 4.0 ± 1.3 h. The mean lag time before absorption commenced was 0.57 ± 0.30 h. The fraction of the dose absorbed ranged from 0.44 to 0.86. Low and/or variable bioavailability of hydroxychloroquine may be a cause of therapeutic failure in some patients. Validation of the deconvolution methods means that these techniques may now be used to assess the bioavailability of hydroxychloroquine in patients. An advantage of these methods is that samples need only be collected over the expected time period of absorption, rather than the whole time drug can be detected in the body, as is required in conventional area under the concentration-time curve ratio methods. Deconvolution studies may be completed in 2 weeks rather than the 10 months required for a conventional bioavailability study of hydroxychloroquine.

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Cited by (37)

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Hydroxychloroquine (HCQ) is an essential drug in the treatment of systemic lupus erythematosus (SLE). This study aimed to detect the concentrations of HCQ and its metabolites from peripheral blood of SLE patients and to investigate the relationship between those concentrations and SLE disease activity.
176 SLE patients treated with HCQ were enrolled in this study. The concentrations of HCQ and its metabolites in their peripheral blood were measured by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Patients’ disease activity was evaluated with the systemic lupus erythematosus disease activity index (SLEDAI). The variables between different concentrations or treatments were statistically analyzed. Linear regression was employed to explore relationships between the concentrations of HCQ and its metabolites with the disease activity.
The SLEDAI was lower in patients with higher concentrations of HCQ, desethylhydroxychloroquine (DHCQ), and desethylchloroquine (DCQ) (P = 0.024, P = 0.018, and P = 0.003, respectively). There were no significant differences in SLEDAI and the concentrations of HCQ and its metabolites among groups with different treatments (P > 0.05). After adjusting age, gender, disease duration, HCQ dose adjusted to actual body weight, and glucocorticoid (GC) dose, the SLEDAI was negatively correlated with the concentrations of HCQ, DHCQ, DCQ and bisdesethylchloroquine (BDCQ) (P = 0.007, P = 0.011, P = 0.029, and P = 0.008, respectively). After grouping analysis, in patients treated with HCQ and GC, the SLEDAI was negatively correlated with concentrations of HCQ, DHCQ and BDCQ (P = 0.011, P = 0.035, and P = 0.036, respectively).
The concentrations of HCQ and metabolites were correlated with the SLE disease activity after adjusting possible confounding factors, indicating that HCQ and its metabolites might play certain immunoregulatory roles in SLE treatment. Moreover, GC might have a synergistic effect with HCQ. It is helpful in clinical management and follow-up to monitor the concentrations of HCQ and its metabolites in SLE patients.
Chloroquine and hydroxychloroquine in the treatment of malaria and repurposing in treating COVID-19
2020, Pharmacology and Therapeutics
Citation Excerpt :
CQ can penetrate into most tissues with a large distribution volume of about 65,000 L and the final elimination half-life 40–60 days (AlKadi, 2007). In contrast, HCQ can accumulate and maintain a steady-state concentration in the body tissues for 4–6 months (Tett, Cutler, & Day, 1992). Both CQ and HCQ undergo biotransformation in the liver by enzymes CYP3A4, CYP2D6, CYP2C8, or CYP1A1. (
Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been commonly used for the treatment and prevention of malaria, and the treatment of autoimmune diseases for several decades. As their new mechanisms of actions are identified in recent years, CQ and HCQ have wider therapeutic applications, one of which is to treat viral infectious diseases. Since the pandemic of the coronavirus disease 2019 (COVID-19), CQ and HCQ have been subjected to a number of in vitro and in vivo tests, and their therapeutic prospects for COVID-19 have been proposed. In this article, the applications and mechanisms of action of CQ and HCQ in their conventional fields of anti-malaria and anti-rheumatism, as well as their repurposing prospects in anti-virus are reviewed. The current trials and future potential of CQ and HCQ in combating COVID-19 are discussed.
Adherence to treatment in systemic lupus erythematosus patients
2013, Best Practice and Research: Clinical Rheumatology
Citation Excerpt :
The interindividual variability of the blood HCQ level (meaning the variability from one patient to another) is important with more than a 10-fold range of drug concentrations found after similar dose administrations. This has been observed in supposedly adherent patients with rheumatoid arthritis [31–33], SLE [34] and in healthy volunteers [35,36]. A relationship between blood concentrations of HCQ and clinical efficacy has been reported in patients with rheumatoid arthritis [31–33], cutaneous lupus [37] and SLE [34,38].
Adherence is defined as “the extent to which a person's behaviour coincides with medical or health advice.” Poor adherence to therapeutic regimens is a common and expensive problem in patients with chronic diseases including systemic lupus erythematosus (SLE) and is associated with a higher risk of flares, morbidity, hospitalisations and poor renal outcome. Non-adherence to the treatment is multifactorial for most patients and varies according to unintentional or intentional patterns. The rates of non-adherence in SLE patients range from 3% to 76% depending on the assessment methods, which are all subject to limitations. Indeed, poor adherence to therapeutic regimens is difficult to evaluate. Two studies have shown that undetectable blood hydroxychloroquine (HCQ) concentration may be a simple, objective and reliable marker of non-adherence in SLE patients. The accurate diagnosis of non-adherence may prevent one from incorrectly interpreting disease manifestations as a lack of response. It may then avoid an unnecessary or even dangerous treatment escalation.
Antimalarials and SLE
2011, Systemic Lupus Erythematosus
Numerous drugs, mainly therapeutic monoclonal antibodies, have been developed for patients with systemic lupus erythematosus (SLE). This chapter mainly focuses on hydroxychloroquine (HCQ) and chloroquine (CQ), which are the best-studied antimalarials used in SLE. The beneficial effects of antimalarials largely exceed their direct effect on SLE activity, especially in patients exposed to side effects of treatments and to atherothrombosis. HCQ and CQ appear to protect against the occurrence of thrombotic events, diabetes, low bone mineral density related to steroids, and even perhaps cancer. Antimalarials have a beneficial effect on lipid profiles of patients with rheumatic diseases, especially those treated with steroids. In general, antimalarials are well tolerated and rarely need to be discontinued because of an adverse reaction. Two types of side effects may be encountered. The first includes gastrointestinal intolerance, aquagenic pruritus, and other cutaneous manifestations. The second type of toxicity is rare but potentially severe and involves various combinations of retinal, neuromuscular, cardiac, and hematological impairments. Discontinuation of the treatment is usually required. The interest of blood HCQ concentration monitoring is important in assessing adherence with treatment. However, the potential benefits of individualized HCQ dosing schedules aimed at maintaining appropriate blood HCQ concentration remains to be demonstrated.
Antimalarials and SLE
2010, Systemic Lupus Erythematosus, Fifth Edition
Numerous drugs, mainly therapeutic monoclonal antibodies, have been developed for patients with systemic lupus erythematosus (SLE). This chapter mainly focuses on hydroxychloroquine (HCQ) and chloroquine (CQ), which are the best-studied antimalarials used in SLE. The beneficial effects of antimalarials largely exceed their direct effect on SLE activity, especially in patients exposed to side effects of treatments and to atherothrombosis. HCQ and CQ appear to protect against the occurrence of thrombotic events, diabetes, low bone mineral density related to steroids, and even perhaps cancer. Antimalarials have a beneficial effect on lipid profiles of patients with rheumatic diseases, especially those treated with steroids. In general, antimalarials are well tolerated and rarely need to be discontinued because of an adverse reaction. Two types of side effects may be encountered. The first includes gastrointestinal intolerance, aquagenic pruritus, and other cutaneous manifestations. The second type of toxicity is rare but potentially severe and involves various combinations of retinal, neuromuscular, cardiac, and hematological impairments. Discontinuation of the treatment is usually required. The interest of blood HCQ concentration monitoring is important in assessing adherence with treatment. However, the potential benefits of individualized HCQ dosing schedules aimed at maintaining appropriate blood HCQ concentration remains to be demonstrated.
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2003, Journal of Theoretical Biology
The metabolic response time, i.e. the delay the system introduces in the response to an input flux, is considered. A novel phenomenological definition is presented, which is valid for any kind of behavior, including transitory or permanent oscillatory responses. In order to calculate the response time of single-input systems, output fluxes have to be deconvoluted with the input flux. The bases for this are established. The resulting function (unit impulse response in time-invariant linear systems) is transformed by subtracting its final state, taking the absolute value and normalizing by the resulting area, so that a norm can be applied that weights the response at every time. This response time can also be interpreted as an average. It coincides with the transition (characteristic) time of an output flux, provided that the input is performed instantaneously (step function). A strictly nonnegative response function is needed for the response time to be interpreted as a mass balance. A simple example is used to study the deviation otherwise. The method is advantageous in that it provides clues on the phenomenological behavior of biochemical systems. For example, deconvolution reveals the intrinsic oscillation-generating mechanism of an allosteric enzyme, which becomes hidden when the input flux increases in a slow way. This is illustrated by means of a model.

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Bioavailability of Hydroxychloroquine Tablets Assessed with Deconvolution Techniques