Abstract: Journal of Pharmacokinetics and Pharmacodynamics
https://doi.org/10.1007/s10928-020-09689-x
(0123456789().,-volV)(0123456789().,-volV)
COMMENTARY
Hydroxychloroquine and azithromycin as potential treatments
for COVID-19; clinical status impacts the outcome
Malek Okour1
•
Mahmoud Al-Kofahi2 • Daren Austin3
Received: 27 April 2020 / Accepted: 4 May 2020
Ó Springer Science+Business Media, LLC, part of Springer Nature 2020
In March 2020, hydroxychloroquine (HCQ) and azithromycin were tested as potential treatments for COVID19 pandemic, in an open label non-randomized clinical trial
[1]. Data were collected from 36 confirmed COVID-19
patients after receiving no treatment (n = 16) or 200 mg
q8h of HCQ with (n = 6) or without (n = 14) azithromycin
depending on clinical status. Collected data over six days
included one HCQ concentration per patient; respiratory
viral loads (PCR assay); azithromycin co-treatment; and
clinical status among other variables.
Using observed HCQ concentrations and basic pharmacokinetic equations, it was possible to calculate missing
concentrations at all days for all patients (Supplementary
Fig. S1). Daily viral load, presented as PCR threshold cycle
(CT), was converted into a dichotomous variable (positivePCR or negative-PCR). A logistic regression evaluated
whether HCQ concentrations, azithromycin co-treatment
(yes/no), clinical status (asymptomatic, upper or lower
respiratory tract infection [URTI or LRTI]), time (day
0–6), and other covariates (age, sex) were associated with
response (positive-PCR outcome).
Electronic supplementary material The online version of this
article (doi:https://doi.org/10.1007/s10928-020-09689-x)
contains supplementary material, which is available to
authorized users.
& Malek Okour
malek.x.okour@gsk.com
Mahmoud Al-Kofahi
malkofah@umn.edu
Daren Austin
daren.j.austin@gsk.com
1
GlaxoSmithKline, Collegeville, PA, USA
2
College of Pharmacy, University of Minnesota, Minneapolis,
MN, USA
3
GlaxoSmithKline, London, UK
Model evaluation and selection was performed based on
statistical significance (p-value B 0.05) and diagnostic
plots (Supplementary Figs. S2, S3). The final model contained HCQ log-concentrations (ng/ml), azithromycin cotreatment, clinical status, and day as statistically significant
covariates (Figs. 1 and S4).
Results showed that the odds of positive-PCR decrease
by 53% for each unit increase in HCQ log-concentration.
Similarly, the odds decrease by 61%, and by 12% for each
day increase, and for azithromycin co-treatment, respectively. Whereas the odds of positive-PCR increase by 99.4
folds and 212 folds for having URTI and LRTI versus
being asymptomatic subject.
Using the model, minimum HCQ concentrations to
achieve [ 50% probability of negative-PCR on day 3 were
calculated, with or without azithromycin, for the clinical
statuses. A minimum HCQ concentration (ng/ml) of 8103
(without azithromycin) and 282 (with azithromycin) are
needed in subjects with LRTI. A minimum HCQ concentration (ng/ml) of 2441 (without azithromycin) and 83.9
(with azithromycin) are needed in subjects with URTI.
Asymptomatic patients require minimal HCQ concentrations (\ 2 ng/ml) regardless of azithromycin co-treatment.
Next, HCQ population PK model [2] was used to simulate dosing regimens needed to achieve targeted HCQ
concentrations. Simulations showed that when HCQ is coadministered with azithromycin, a loading dose is critical
in rapid achievement of targeted concentrations. The suggested..
{ 'indexed': { 'date-parts': [[2023, 12, 27]],
'date-time': '2023-12-27T06:00:43Z',
'timestamp': 1703656843769},
'reference-count': 2,
'publisher': 'Springer Science and Business Media LLC',
'issue': '3',
'license': [ { 'start': { 'date-parts': [[2020, 5, 13]],
'date-time': '2020-05-13T00:00:00Z',
'timestamp': 1589328000000},
'content-version': 'tdm',
'delay-in-days': 0,
'URL': 'https://www.springer.com/tdm'},
{ 'start': { 'date-parts': [[2020, 5, 13]],
'date-time': '2020-05-13T00:00:00Z',
'timestamp': 1589328000000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://www.springer.com/tdm'}],
'content-domain': {'domain': ['link.springer.com'], 'crossmark-restriction': False},
'published-print': {'date-parts': [[2020, 6]]},
'DOI': '10.1007/s10928-020-09689-x',
'type': 'journal-article',
'created': {'date-parts': [[2020, 5, 13]], 'date-time': '2020-05-13T11:02:28Z', 'timestamp': 1589367748000},
'page': '187-188',
'update-policy': 'http://dx.doi.org/10.1007/springer_crossmark_policy',
'source': 'Crossref',
'is-referenced-by-count': 15,
'title': 'Hydroxychloroquine and azithromycin as potential treatments for COVID-19; clinical status '
'impacts the outcome',
'prefix': '10.1007',
'volume': '47',
'author': [ { 'ORCID': 'http://orcid.org/0000-0002-4739-4989',
'authenticated-orcid': False,
'given': 'Malek',
'family': 'Okour',
'sequence': 'first',
'affiliation': []},
{'given': 'Mahmoud', 'family': 'Al-Kofahi', 'sequence': 'additional', 'affiliation': []},
{'given': 'Daren', 'family': 'Austin', 'sequence': 'additional', 'affiliation': []}],
'member': '297',
'published-online': {'date-parts': [[2020, 5, 13]]},
'reference': [ { 'key': '9689_CR1',
'doi-asserted-by': 'publisher',
'first-page': '20',
'DOI': '10.1016/j.ijantimicag.2020.105949:105949',
'volume': '20',
'author': 'P Gautret',
'year': '2020',
'unstructured': 'Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M et al '
'(2020) Hydroxychloroquine and azithromycin as a treatment of COVID-19: '
'results of an open-label non-randomized clinical trial. Int J Antimicrob '
'Agents 20:20. https://doi.org/10.1016/j.ijantimicag.2020.105949:105949',
'journal-title': 'Int J Antimicrob Agents'},
{ 'issue': '4',
'key': '9689_CR2',
'doi-asserted-by': 'publisher',
'first-page': '1468',
'DOI': '10.1128/AAC.00339-08',
'volume': '53',
'author': 'HS Lim',
'year': '2009',
'unstructured': 'Lim HS, Im JS, Cho JY, Bae KS, Klein TA, Yeom JS, Kim TS, Choi JS, Jang '
'IJ, Park JW (2009) Pharmacokinetics of hydroxychloroquine and its '
'clinical implications in chemoprophylaxis against malaria caused by '
'Plasmodium vivax. Antimicrob Agents Chemother 53(4):1468–1475',
'journal-title': 'Antimicrob Agents Chemother'}],
'container-title': 'Journal of Pharmacokinetics and Pharmacodynamics',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1007/s10928-020-09689-x.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://link.springer.com/article/10.1007/s10928-020-09689-x/fulltext.html',
'content-type': 'text/html',
'content-version': 'vor',
'intended-application': 'text-mining'},
{ 'URL': 'https://link.springer.com/content/pdf/10.1007/s10928-020-09689-x.pdf',
'content-type': 'application/pdf',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2021, 5, 12]],
'date-time': '2021-05-12T23:24:36Z',
'timestamp': 1620861876000},
'score': 1,
'resource': {'primary': {'URL': 'https://link.springer.com/10.1007/s10928-020-09689-x'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2020, 5, 13]]},
'references-count': 2,
'journal-issue': {'issue': '3', 'published-print': {'date-parts': [[2020, 6]]}},
'alternative-id': ['9689'],
'URL': 'http://dx.doi.org/10.1007/s10928-020-09689-x',
'relation': {},
'ISSN': ['1567-567X', '1573-8744'],
'subject': [],
'container-title-short': 'J Pharmacokinet Pharmacodyn',
'published': {'date-parts': [[2020, 5, 13]]},
'assertion': [ { 'value': '27 April 2020',
'order': 1,
'name': 'received',
'label': 'Received',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '4 May 2020',
'order': 2,
'name': 'accepted',
'label': 'Accepted',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': '13 May 2020',
'order': 3,
'name': 'first_online',
'label': 'First Online',
'group': {'name': 'ArticleHistory', 'label': 'Article History'}},
{ 'value': 'This content has been made available to all.',
'name': 'free',
'label': 'Free to read'}]}
