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The Association between Cigarette Smoking and Efavirenz Plasma Concentration using the Population Pharmacokinetic Approach
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  • Ngah Kuan Chow,
  • E-Jinq Wong,
  • Lee Lee Low,
  • Siti Maisharah Sheikh Ghadzi,
  • Sabariah Noor Harun,
  • Amer Hayat Khan
Ngah Kuan Chow
Hospital Kulim, Universiti Sains Malaysia

Corresponding Author:[email protected]

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E-Jinq Wong
Hospital Sultanah Bahiyah
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Lee Lee Low
Hospital Sultanah Bahiyah
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Siti Maisharah Sheikh Ghadzi
Universiti Sains Malaysia
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Sabariah Noor Harun
Universiti Sains Malaysia
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Amer Hayat Khan
Universiti Sains Malaysia
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Aim: Efavirenz is still widely used as the preferred first-line antiretroviral agent in the middle- and low- income countries, including Malaysia. The efavirenz population pharmacokinetic profile among HIV-positive smokers is still unknown. We aimed to assess the association of smoking with efavirenz and the differences in HIV clinical outcomes. Methods: A total of 154 stable HIV-positive patients on efavirenz in northern Malaysia were recruited with a sparse sampling for this multicentre prospective cohort study. The association between smoking and efavirenz pharmacokinetic parameters was determined using the non-linear mixed-effect model (NONMEM). A mixture model of clearance was adopted to describe the metaboliser status because genetic data is unavailable. The effect of smoking on HIV clinical markers (CD4, CD4 / CD8 ratio and viral blips) for at least two years after the antiretroviral initiation was also investigated. Results: Our data were best fitted with a one-compartment mixture model with first-order absorption without lag time. Smoking significantly associated with higher clearance (CL/F) (β = 1.39; 95% confidence interval (CI): 1.07 to 1.91), while weight affected both CL/F and volume (V/F). From the mixture model, 20% of patients were in the slow clearance group, which mimic the genotype distribution of slow metaboliser. An efavirenz dose reduction is not recommended for smokers ≥60kg with normal metabolism rate. Smoking significantly associated with slower normalisation of CD4 and CD4 / CD8 ratio. Conclusion: HIV-positive smokers presented with significantly higher efavirenz clearance and unfavourable clinical outcomes. Close monitoring of adherence and clinical response among smokers is warranted.
23 Nov 2020Submitted to British Journal of Clinical Pharmacology
24 Nov 2020Submission Checks Completed
24 Nov 2020Assigned to Editor
10 Dec 2020Reviewer(s) Assigned
11 Jan 2021Review(s) Completed, Editorial Evaluation Pending
18 Jan 2021Editorial Decision: Revise Major
02 Feb 20211st Revision Received
03 Feb 2021Submission Checks Completed
03 Feb 2021Assigned to Editor
03 Feb 2021Review(s) Completed, Editorial Evaluation Pending
13 Feb 2021Editorial Decision: Accept